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The literature related to novel delivery systems for the treatment o f vitiligo have been

extensively reviewed and compiled as follov/s.

2.1. Patents on Treatm ents o f V itiligo:

WO/2005/011676 made a composition that can be used as cosmetic medicine and which

is useful for the treatment of lesions caused by vitiligo. The inventive composition

contains L-proline amino acid as active ingredient, which can stimulate the synthesis o f

melanic pigment of the skin as well as the reproduction of melanocites and has no severe

side effects as shown in the toxicological and clinical tests (Miyares et a l, 2004). The

technical aim of the invention was to provide a synthetic product which is useful for the

treatment of vitiligo, has no toxic effects and shows the absence o f relapse o f the disease.

VÔ/2001/062205 invented a method o f treating vitiligo by using an excimer laser which

emits light in the UVB range and also disclosed a method of increasing exposure o f

affected areas to restore pigmentation. This approach was attempted to overcome the

drawbacks of topical preparations, topical PUVA treatment, oral PUVA treatment and

UVB phototherapy. Topical preparations tend to rub-olT and have limited value in areas

such as the lower neck, wrists and hands, More over they do not attempt to treat vitiligo,

but simply mask the affected areas with the surrounding skin (Freedberg et al., 1999),

Another treatment for vitiligo attempts to increase the effect o f UVA light is PUVA in

which the patient applies psoralen topically to the affected areas, and then stands inside

the phototherapy unit for exposure to the UVA light emitted by conventional tube-style

bulbs to gain the combined actions of psoralen and UVA (Spencer et a l, 2001). Major

drawbacks of PUVA treatment is that the exposure of whole body rather than vitiligo

areas which may lead to the risk of skin cancers, erythema, blistering and hyper

pigmentation of the surrounding unaffected areas also. Regimentation is seen in only

about half of treated patients (Westemof et a l, 1997). The present invention, however,

treats only those skin areas afflicted with vitiligo and thus minimizes the risk o f skin

cancers and other side effects. It is less time consuming, and has higher success rate.

Phototherapy with UV-A radiation and oral psoralens is another known treatment. UV-A

irradiation occurs at intervals of two to three times weekly and is generally maintained

for months to gi'eater than a year (Elliott et al,, 1959, Fatah et al., 1969 and Ortonne.,

CHAPTER 2 LITERATURE REVIEW 1 2 7

DEPARTMENT OF PHARMACEUTICS JAMIA HAMDARD

1989). Moreover, side effects o f this tyjie o f PUVA include burning, nausea, erythema,

lentigenes, pruritus, and cataracts. UVB phototherapy is much more effective at

stimulating melanocytes than PUVA. However, regular UVB light cannot penetrate the

skin deeper than the epidermis, and hence is completely ineffective in stimulatiHg the

deep melanocytes underneath patches o f vitiligo. The present invention overcomes this

problem in the prior art through the use o f an'excimer laser which emits laser light in the

ultraviolet range and provides higher energy thereby decreasing the treatment time (Yu et

a l, 1999) . This method o f treating vitiligo is confined to segrnentai-type vitiligo, which

is vitiligo caused by dysfunction o f nerves. Lasers have also been used to treat vitiligo to

aid in skin grafting.

DE 1020D6042529A1 had studied about the UV isTadiator, which has a miniaturized

lamp with electrodes serves simultaneously as reflector, operating electronics for

operating the lamp, and an adapter that was arranged in fi'ont o f a radiation outlet

window, where the irradiator is so handy that the irradiator is suitable as tool holder for

manual application to the patient (Ernesti Karsten., 2008). The electronics is integrated

into the tool holder, where the waveguide was adapted as an easily replaceable adapter to

the radiation outlet window for the treatment o f vitiligo.

US 2007§27080A1 explained about the synergistic effects o f basic fibroblast growth

factor for the treatment o f vitiligo. A hypothesis, postulated that deficiency o f mitogen

like basic fibroblast growth factor (bFGF) in the skin could result in the loss o f

melanocytes (melanin producing cells) which leads to vitiligo. Basic fibroblast growth

factor (bFGF) or FGF2 is a potent mitogen for variety o f cell types including melanocytes

and also contains large number o f basic amino acid residues (Lysine, Ai'ginine and

Histidine). It was found in a wide variety o f tissue types including placenta, keratinocytes

and fibroblasts. The bFGF or its agonist peptides were tested on human volunteers in the

various phases o f clinical trials in India and found to be successful in repigmenting about

80% o f volunteers with stable generalised vitiligo and segmental vitiligo. The major

therapies for the treatment o f vitiligo are Psoralen plus UV-A which is effective in about

50% o f cases, steroids has certain effects in the case o f fast spreading vitiligo and often

CHAPTER 2 LITERATURE REVIEW 1 28


reoccurs on stoppage of treatment. Surgical treatment is the last resort fi)r vitiligo, when

all other option fails. Basic fibroblast growth factor peptide(s) lotion was developed as a

new mode of therapy for the treatment o f vitiligo (US 2007027080A1). The

combinatorial treatment o f vitiligo by local application o f bFGF peptide(s) lotions in

association u'ith psoralen and UV-A, or steroids or surgical procedures produce

synergistic response and that the rate o f repigmentation increases synergistically and

more effective results are obtained than with any o f them alone.

WO/2006/088310 explained an invention related to a pharmaceutical composition for the

prevention and treatment o f vitiligo comprising retinoid as an effective ingredient.

Retinoic acid has been used as an anti-acne drug. In addition, retinoic acid works vi ell in

lightening o f pigment by reducing adhesion o f melanocytes, inhibits proliferation o f

meIanoc>tes (Fligiel et a!., 1992) and reduces dendrites o f melanocytes, so that it is also

used for the treatment o f melasma (Ortonne., 1992). Retinoic acid can, reduce skin

atrophy caused by corticosteroid, it is expected for retinoic acid to inhibit side effects

carried by corticosteroid. Therefore, a pharmaceutical composition containing retinoid as

an active ingredient was prepared. The preparation not only prevents skin atrophy by

corticosteroid but also proliferates human keratinocytes and inhibits apoptosis to up-

regulate SCF and other melanocyte growth factors, so that it is effectively used for the

treatment o f vitiligo by increasing melanocytes with restoring pigment. It can also induce

melanocytes proliferation and increase coloring effect o f the cells (Chey et al., 2006). It

was claimed that pharmaceutical composition o f this invention containing retinoid as an

effective ingredient not only prevents skin atrophy caused by corticosteroid, a

conventional treatment agent o f vitiligo, but also inhibits apoptosis o f melanocytes and

thus improving pigmentation, so that it can be effectively used for the prevention and

treatment o f vitiligo.

Young et a l in WO/2005/067405 described an invention related to methods and kits for

screening responsiveness to drugs effective in treatment or prevention o f vitiligo. It was

claimed tliat methods and kits for screening active ingredients effective in treatment or

prevention o f vitiligo, and methods and kits for prognosis o f vitiligo using eukaryotic

CHAPTER 2 LITERATURE REVIEW 29


translation initiation factor 4A1 (eIF4Ar) gene, ribosoma! protein L I3 (L I3) gene and

mediator o f RMA polymerase to transcription (MRT) gene (Lee et a l, 2005). The

responsiveness to drugs used for treatment or prevention o f skin diseaties which requires

the administration o f corticosteroids was investigated. Preferabiy, drugs are selected fi'orn

tlie group consisting of all- trans-retinoic acid (ATRA), vitamin C, trichloroacetic acid,

and calcipotribl. Most preferably, the drug is ATRA.

US 5690966 claimed a process for the preparation-of an extract from human placenta

containing glycosphingolipids and endothelin-like peptides useful for the treatment of

vitiligo which comprises extracting the whole triturated human placenta by heating in a

phased manner, first at about 40.-50C for about 20-40 minutes and then at about 60.”

70 C for about 5-15 minutes, avoiding the application o f direct heat (Bhadra et a!., 1997).

US 6451358 invented a compositions and methods for the treatment o f vitiligo. The

composition consists of one or more herbal ingredients like Eciipta prostrata L.,

Angelica dahurica {Fish. ex. Hoffni), Polygonum multiforum Thumb, Astragalus

complanalus, Tribulus terre.slris L., Lithospermum erythrorhizon sieb et zucc, Paris

peiiolata (Bak. ex Forb), Salvia multiarrhiza Bge, Sophora flavescens Ait, Atractylodes

lancea (Thumb) Do, or their mixtures. The method comprises treating the vitiligo by

giving this composition to the patient tlii'ough oral route (Huiping Zhao., 2002). The

treatment may be further improved by applying topically to the affected areas, any one o f

the following preparations such as, sulfur and kerosene, Nevlum oporum solund and

alcohol, a preparation o f Cinnamomum cassia presl, Psoralea corylifalia L., alcohol and

water and a preparation of Portulaca oleracea L., brown sugar, and vinegar.

EP 1747786A2 proved the effect o f natural ingredients with anti-vitiligo properties by

applying it in white patches o f depigmentation present in the skin. There are evidences

states about the pathogenic association between vitiligo and the increase in epidennal

oxidative stress, mechanism underlying the functional alterations in the melanocytes and

vitiligo development (Paleo and Rojas., 2007). This treatment does not allow any

synthetic drugs to be incorporated in the formulation other than natural products with


D E P A R T M E N T OF PH A R M A C EU T IC S lAMlA HAMDARD

anti-vitiligo properties. It contains the water extract o f Pimienta racemosa as active

ingredients, this inhibits neutrophil chemotaxis and sirperoxide anion production and acts

as antioxidant on the skin with vitiligo, promoting the restoration o f the afl'ected area.

Moreover, it contains watery extract of melon, which supplies antioxidant enzymes like

catalase and superoxide disniutase, these antioxidant enzymes are free radicals

scavengers present in melanocytes. Coenzyme Q-!0 is other active ingredient, which

helps these enzymes to develop their function besides having antioxidant properties, and

plays an important role in the production of ceil energy, and therefore it is an important

mitochondrial and immunological stimulator. It also contains pyridoxiiie, which is

necessary for the metabolism of amino acids like tyrosine and phenylalanine which

participate in melanin production and the lemon terpene which contains ascorbic acid

which also acts as an antioxidant inhibiting fi'ee radicals. Its formula is given by 1:1 of

watery extract of Pimienta racemosa; 1:2 of watery extract o f Ciicumis melo, 100 ml o f

extract o f Citrus aurantifolia, 100 mg Coenzyme Q-10 and 100 rng Pyridoxiiie

Chlorhydrate and also contains 100 g o f excipients which contains iinibase cream,

eucalyptus essential oil, propyieneglycol, glycerine, cetylic alcohol, nipagin and iiipazol.

WO/2008/098325 described the use of one or many parts o f plants or extracts o f plants or

pure isolated compounds ol' plants from tlie species o f Stachytarphela cayensensis, S.

jarnaicensis and .S’, eliotis (Verbenaceae family) in different ratios incorporated together

in the form o f tablets and capsules for oral route or in the form o f emulsions, creams,

gels, liposomes, microcapsules, nanoparticles, aerosols, ointments and slow release

implants for topical application which can be used for the treatment o f vitiligo (Queiroz

Ferreira., 2008). Through pre-clinical and clinical tests, it has been proven that the

identified compounds are used as part o f formulae to treat vitiligo, used by oral route

when in tablets or capsules, and by topical route as dyes, creams, gels, aerosols or similar

others used as adjuvant. This invention also extends to the pharmaceutical compositions

containing, besides the referred extracts, fractions or components of those extracts

(natural or synthetic), used to formulate medications applied on the treatment or

prophylaxis of vitiligo.

CHAPTER 2 LITEFÂTIJRE REVIEW 31

DEPARTMENT OF PHARMACEUTICS . |AM!A HAMDARD


Table 2,1; Summary of Patents:

Patenfs Actives Benefits Draw backs

W0/2005/0!1676L-S>roline amino acid

No toxic

effects, absence

of relapse of

vitiligo

Rub ofl', tedious to

apply in areas like eye

lid.

WO/2001/062 205Psoralen and UVB

Exposed only to

the affected

skin

Risk of side effects

DE 102006042529A1UV irradiator Patient

compliance

Risk of side effects

US 2007027080A1Basic fibroblast growth factor

peptide(s) + other therapies

Synergistic

effect

Rub off, tedious to

apply in areas like eye

lid.

WO/2006/088310 Retinoid (retinoic acid) - Fonmlation stability

US 5690966Glycosphingolipids and

endothelin-iike peptides-

Formulation stability

US 6451358

Eclipla proslmta L„ Angelica

clahurica. Polygonum

mulliforum thumb, Astragalus

complanatus, Tribidus

terrestris L., Lithospermum

erythrorhizon sieb et zucc,

Paris petiolata, Salvia

multiorrhiza Bge, Sophora

flavescens Ait, Atractylodes

lancea.

-

No risk of side effects

EP 1747786 A2

Pimienta racemosa, watery

extract of melon, Coenzynie

Q-10, pyridoxine and lemon

terpene

No risk o f side effects

WO/2008/098325

Stachytarpheta cayensensis, S.

jamaicensis and S. eliotis

(Verbenaceae family)

-

No risk of side effects

2.2. Recent Developments in Sustained Release Drug Delivery

Mohsen et al.. (2012) fonnulated sustained release matrix tablets of aceclofenac with

Eudragit® RSPO and Eudragit® RLPO were prepared using three techniques; direct

compression, wet granulation and solid dispersion. The most optimum matrix fbnnula

was manipulated by addition of an immediate release layer for prompt release of the

dmg. All tablets were evaluated regarding their physical properties and in-vitro release

DEPARTMENT OF PHARMACEUTICS JAMIAHAMDARD

over 24 hours. In-vitro release studies revealed that Eiidragit RSPO retarded the release

more than Eudragit RLPO and solid dispersion was the most suitable preparation

technique. The double layer tablet was successful in prolonging drug release up to 24

hours. Pharmacokinetic studies in albino rabbits were conducted for tlie optimized

formula (Registration No, PI-260). The results o f pharmacokinetic studies showed that

double layer tablet exhibited longer MRT when compared to the commercial brand o f

aceclofeiiac immediate release tablet (Bristaflam®), demonstrating the sustained release

properties.

Pâtfiraj et a i, (2011) fornuiiated a control release oral delivery system and investigated

the influence o f different diluents, Carbopoi 934P concentration and granulation

technique in the release o f poorly water-soluble drug (Ibuprofen) from Carbopoi 934P

matrix tablets. Matrix tablets were prepared by direct compression, wet granulation and

dry granulation method at different polymer concentration using lactose, dibasic calcium

phosphate (DCP), microcrystalline cellulose (MCC) and starch as diluents. Dissolution

studies were canied out in 900 ml phosphate buffer pH 7.4 using USP-apparatus I. At 5%

Carbopoi 934P concentration, the was found in the rank order o f tablets containing

starch<MCC<DCP<lactose. Granulation technique had appreciable effect on drug release

profde which was in the rank order of direct compression<dry granulation<wet

granulation (alcohol) <wet granulation (water). There was a significant effect of

granulation technique, polymer concentration in the drug (Ibuprofen) release rate from

Carbopoi 934P matrix based tablets (ANOVA, p<0.05). Diluents have appreciable effect

on drug release rate only at low polymer concentration.

Ahammad et a i , (2011) described the effect o f different percentages o f a hydrophilic

polymer and impact of granulation technique on the release profde o f gliclazide from

matrix system. In their study, matrix tablets o f Gliclazide were prepared by both direct

compression and wet granulation process using methocel K15M CR. Release kinetics o f

gliclazide matrix tablets were determined using USP paddle method at Phosphate buffer

(pH 7.4). They found that, at lower concentration o f polymer (15%) most o f the

formulation tends to Higuchi release kinetics and at higher concentration (30%), the


DEPARTMENT OF PHARMACEUTICS }AMIA HAMDARD

release tits well with Zero order kinetics. 30% of polymeric content in the matrix tablets

decreased the rate o f the drug due to increased tortuosity and dec4*eased porosity. The

effect of granulalion process on drug release were also studied and they found that wet

granulation extend the release more than that o f the direct compression technique.

Zaicl et aL, (2011) compared the quality o f Valzan R tablet (160 mg, valsartao immediate

release test formulation) and its pharmacokinetic parameters with Diovan R tablet (160

mg, vaisartai'i reference formulation). Valzan R tablets were prepared according to a dry

granulation method (roll compaction). To assess the bioequivalence o f Valzan R tablets a

randomized, two-way, crossover, bioequivalence study was performed in 24 healthy male

volunteers. The selected vohmteers were divided into two groups o f 12 subjects. One

group was treated with the reference fonnulation (Diovan R) and the other one with the

generic Valzan R, with a cross-over after the drug washout period o f 14 days. Blood

samples were collected at fixed time intervals and valsartan concentrations were

detennined by a validated HPLC assay method. The pharmacokinetic parameters

AUC0.48, AUCO, Cmax, Trnax, Ke and Tl/2 were determined for both the tablets and

were compared statistically to evaluate the bioequivalence between the two brands o f

valsartan, using the statistical model recommended by the FDA. The analysis o f variance

(ANOVA) did not show any significant difference between the two fbrmuiations and

90% confidence intervals (Cl) fell within the acceptable range for bioequivalence. Based

on their statistical evaluation it was concluded that the test tablets (Valzan R) exhibits

pharmacokinetic profile comparable to the reference brand Diovan.

Sunitha et a i, (2011) investigated, hydrotropic solution o f sodium citrate (O.OIM) as

solubilizing agent to solubilize valsartan (poorly water soluble drug) fine powder and its

tablet dosage form for spectrophotometric determination in UV region. Valsartan showed

maximum absorbance at 250 nm and followed Beer’s law in concentration range o f 5-30

mcg/mL. Results of analysis were statistically validated for linearity, precision, LOD, and

LOQ. The proposed method was new, simple, accurate, reliable, economic and can be

employed in routine to analyze Valsartan tablets. Either hydro tropic agent or commonly

used tablet additives did not interfere in analysis.

C H A P T E R 2 LlTFillA TlJRE R E V IE W 134-

D E P A R T M EN T OF PHA RM A CEUTICS JA M IA H A M D A R D

Mahajais et a!., (2011) developed antiliypertensive sustained release matrix tables of

valsartan Angiotensin 0 receptor antagonist, using hydroxypro}3ylmethylceilulose alone

and in combination with ethyl cellulose as the matrix material in different proportion by

wet granulation method. The granules showed satisfactory flow properties,

compressibility and all the tablet formulations showed acceptable pharniacotechnical

properties. In vitro dissolution studies indicate that EC signitlcantly reciuced the rate of

drug release compared to HPMC. But no significant difference was observed in the

release profde of matrix tablets made by higher percentage of EC. The result of

dissolution study indicate that the formulation prepared by low viscosity grade HPMC

showed maximum drug release up to 8 hrs and high viscosity greed HPMC and EC

formulation showed up to 12 lirs. Mathematical treatment o f the in vitro drug release

data suggests that, optimized formulation fitted in to Korsmeyer and Peppas release

kinetic shows R2 value 0.9930. I3rug release from the matrix occurred by combination of

two mechanism, diffusion and erosion o f tablet.

Rajii et ai., (2 0 1 1 ) developed a rapid, precise, accurate, specific and sensitive reverse

phase liquid chromatographic method for the estimation o f valsartan in pure and tablet

formulation. The chromatographic method was standardized using a Xtcrra C l 8 column

(100x4.6 mm I.D., 5 pm particle size) with UV detection at 210 nm and flow rate o f 1

ml/min. The mobile phase consisting o f a mixture o f phosphate buffer pH 3 and

acetonitrile in the ratio of 50:50 v/v was selected. The proposed method was validated for

its sensitivity, linearity, accuracy and precision. The retention time for valsartan was

4.450 min. The % recovery was within the range between 98.6 % and 101.2 %. The

percentage RSD for precision and accuracy o f the method was found to be less than 2 %.

This method can be employed for routine quality control analysis of valsartan in tablet

dosage forms.

Kumar et al., (2011) developed a simple method for the estimation o f Valsartan in bulk

and pharmaceutical dosage forms. Methanol was chosen as the solvent system. The A-max

was found to be 249nm and all absorbance values were carried out at 249nm.The

responses were linear in the range o f 5-lOOpg/mLThe regression equation o f the

CHAPTER 2 LlTEflATURE REVIEW 35


calibration graph and correlation coefficient were found to be y = ().028x - 0 . 0 0 1 and

0.999 respectively. The %RSD values for both intraday and interday precision were !e5;s

than 1%. The recovery o f the drug fi-om the sample was ranged between 97.77% and

101.4%. The proposed method was validated fbr accuracy, precision, robustness,

ruggedness, LOD and LOQ. Commercial tablets containing 40mg and 80mg o f valsartan

were analysed by the proposed method and the results were well witliin the claimed

limits. Furthermore stability studies o f valsartan were carried out under acidic, alkaline,

hydrolytic, thermol>l.ic, oxidation, photoiytic and LfV degradation conditions as per

SIAM (Stability Indicating Assay Methods).

Raman et a!., (2011) prepared nifedipine solid dispersions in cross carmellose sodium

(CCS) and sodium starch glycholate (SSG) and were investigated with a view to design

sustained release tablets. As nifedipine is practically insoluble in water and aqueous

fluids, its solid dispersions in CCS and SSG has markedly enhanced the dissolution rate

of nifedipine. Matrix tablets formulated employing nifedipine dispersion in CCS and SSCi

with gum olibanum alone and in combination with rnethocel KM. The matrix tablets

controlled and complete release over a period of 12 hrs. Drug release o f their tablets

followed first order kinetic and the release was diffusion controlled.

Afsar et a l, (2011) developed once daily sustained release tablets of Aceclofenac by wet

granulation using HPMC K-100. The tablets were subjected to physicochemical studies,

in vitro drug release, kinetic studies and stability studies. FTIR studies shown there were

no interaction between drug and polymers. The dmg release from optimize formulation

was extended for period of 24 hrs. The kinetic release follows zero order models.

Stability studies for optimize formulation tor one month at 45° C with RH 75 ± 5% and

showed there was no significant change in drug content. Their study indicated the

suitability o f hydrophilic polymers in the preparation o f matrix based sustained release

formulation o f Acelofenac.

Gancle et al., (2011) investigation efforts were made to improve the bioavailability o f

baclofen by increasing the residence time o f the drug through sustained-release matrix



tablet formulation via gastroreteiitive mechanism. Tablets were prepared by wet

granulation technique. I'lie influence of gas generating and gel forming agents, araoiiiit o f

baclofen and total weight o f tablet on physical properties, in vitro buoyancy, floating lag

time, drug release, DSC, X-ray studies were investigated. The release mechanisms were

explored and explained by applying zero order, (irst order, Higiichi and Korsmeyer

equations. The selected formulations were subjected to stabihty study for the period o f

three months. For all formulations, kinetics o f drug release from tablet followed

Higuchi’s square root o f time kinetic treatment heralding diffusion as predominant

mechanism of drug release.-* X-ray imaging in six healthy human volunteers revealed a

mean gastric retention period o f 5.50 ± 0.7 hrs for the selected tbrmulation. Stable,

sustained release effervescent floating matrix tablets o f baclofen coiiid be prepared by

wet granulation technique.

Jofliieswari ei al., (2011) described a new, simple, accurate and sensitive UV-

spectrophotometric absorption correction method has been developed foi‘ simultaneous

determination o f amlodipine besylate, valsartaii and hydroch]orothia2 ide in bulk and in

combined tablets dosage ibrrn. The stock solutions were prepared in methanol followed

by the further required dilution with distilled water. The method was based upon direct

estimation o f amlodipine besylate at 365 nm, as at this wavelength hydrochlorothiazide

and valsartan have zero order absorbance and show no interference. For estimation o f

hydrochlorothiazide, cotiected absorbance was calculated at 315 nm due to the

interference o f amlodipine besylate and valsartan has zero absorbance at this wavelength.

At 250 nm, these three drugs showed absorbance. To estimate the amount of valsartan,

the absorbance of amlodipine besylate and hydrochlorothiazide were corrected for

interference at 250 nm by using absoiptive values. Beer’s law obeyed the concentration

range o f 1 -32 meg/ Ml, 4 - 4 0 meg / mL and 2 - 20 meg / mL for amlodipine besylate,

valsartan and hydrochlorothiazide, respectively. The developed method was validated

according to ICH guidelines and it found to be accurate and precise. Thus the proposed

method can be successfully applied for simultaneous determination o f amlodipine

besylate, valsartan and hydrochlorothiazide in bullc and in combination tablets dosage

fonn.



Krislinamooii'hy el: at., (2(111) enhanced the aqueous solubility o f olanzapine byusing

the Solid dispersion technique. Solid dispersionj; of olanzapine were prepared by the

dispersion method using using PGS and SSG as carriers. Characterization was done by

phase solubility, in-vitro release, saturation solubility, pemieation, wettability, XRD and

FTIR analysis. Solid dispersions showed Irigher solubility and an improved drug release

profile tlian the pure drug. Solid dispersion and physical mixture with a drug-polyiiner

ratio o f 1:10 showed the best release profde in comparison with the other samples. Phase

sokdiility results verified the solubilization effect of the carrier. XR I) and NIR analysis

confirmed the reduction o f crystallinity in the samples. The release study findings were

well supported by the results o f wettability, saturation solubility and permeability studies.

IR aiialysis substantiated the inertness o f the carrier. It was concluded that pregelatinised

starch (PGS) and sodium starch glycolkite (SSG) could be utilized as effective can'iers to

improve the aqueous solubility o f poorly soluble drugs.

Wacliier et al., (2011) formulated an oral sustained release metformin tablet prepared by

direct compression method, using hydrophilic Eudragit RSiÔ and RLPO alone or in

combination with hydrophobic ethyl cellulose polymer as rate controlling factor. All the

batches were evaluated for thickness, weight variation, hardness, and drug content

uniformity and in vitro drug release. Mean dissolution time is used to characterize drug

release rate fi-om a dosage form and indicates the drug release retarding efficiency o f

polymer. When Eudragit RSPO and RLPO were used alone as the only retarding

polymer, a sustained drug release pattern were not observed while, Inclusion o f

ethylcellulose in the matrix almost doubled ( 1 2 h) the time required for releasing the

drug. Kinetic modeling o f in vitro dissolution profiles revealed the drug release

mechanism ranges fi'om diffusion controlled to anomalous type. Fitting the data to

Korsmeyer equation indicated that difftision along with erosion could be the mechanism

of drug release. .

Vidyadhara et a!., (2011) formulated solid dispersions o f Glimepiride with sodium

starch glycolate(SSG) were prepared and further compressed as tablets by using diluents

such as lactose, dicalcium phosphate and microcrystalline cellulose. The solid dispersions

CHAPTER 2 LITERATURE REVIEV^ 3 8


of Glirnepiride with SSG at different ratios were prepared by physical mixing, solvent

evaporation and kiieciding methods. The rapid release o f poorly soluble Glirnepiride /rom

solid dispersions was influenced by the proportion o f polymer and the method employed

for its preparation. Among the three methods employed solvent evaporation and kneading

methods were found to be suitable for improving the dissolution rate o f Glirnepiride. The

release was found to follow the first order kinetics. Some of the dispersions prepared by

the solvent evaporation method and kneading method were formulated into tablets with

diluents such as lactose, DCP and MCC. All the tablet preparations containing diluents

were found to release the drug in the order o f DCP> MCC > Lactose.

IRaniana ct a l, (2 0 1 1 ) prepared nifedipine solid dispersion incross carmellose sodium

(CCS) and sodium starch glycolate (SSG) and were investigated with a view to design

sustained release tablets o f nifedipine. As nifedipine is practically insoluble in water and

aqueous fluid; its solid dispersion in CCS and SSG has markedly enhanced the

dissolution rate o f nifedipine. Matrix tablets formulated employing nifedipine dispersions

in CCS and SSG with gum olibanom alone and in combinations with methoeel K4 M. The

matrix tablets gave slow, controlled and complete release over a period of 12 hrs. Drug

release from these tablets followed fu'st order kinetics and the release was diffusion

controlled. The (n) values obtained from Peppas plots were within the range o f 0.45 to

0-9, indicates the drug release by both diffusion coupled with erosion. The DSC studies

were also indicating the absence o f strong interactions between the components and

. suggesting drug - excipient compatibility in all the formulations examined.

Mullaicharam et aL, (2010) developed once-daily sustained release matrix tablets o f

metoprolol tartrate with inlay hydrochlorothiazide tablet as an immediate release

formulation. The inlay tablets were prepared by wet granulation method using hydroxy

propyl methylcellulose in various percentages. The drug-excipient incompatibility studies

were performed by Differential Scanning Calorimetry(DSC).The granules showed

satisfactory flow properties and compressibility. The m vitro and the in vivo release

studies in rabbit were performed. The mechanism of drug release was diffusion coupled

with erosion.

CHAPTER 2 LITE'Ri\TURE REVIEW 3 9


Shanthi et al,, (2010) stated the Captopril provides effective treatment for hypertension

and congestive heart failure. Development o f a proloeged action dosage form for

captopril will bring many benefits. The development o f oral controlled or sustained

captopril formulations has been a challenge for a long period o f time. The reason being

tlie drug i,s highly water soluble, unstable in alkaline intestinal pH and decrease in

bioavailability in presence of food. Various attempts liave been made to regulate the

release and increase the bioavailability of the drug.

Aiiroop et a l, (2010) stated The Hydroxy propyl methyl cellulose'{HPMC) is generally

combined with hydrophobic polymers in fabricating ora! controiled solid dosage forms.

This study evaluated the utility o f diverse grades o f HPMC in developing a controlled

release formulation for a hydrophilic drug, enaiapril maleate. Two grades o f HPMC

(KlOO and K4M) in different proportions were used to prepare the tablets, all the

formulations demonstrated good physical integrity and the drug content were in the

official limits.

K un ia ii et a i, (2 § 1 0 ) designed and evaluated sustained-release matrix once-daily

formulation of Stavudine, to increase therapeutic efTicacy, reduce frequency of

administration and improve patient compliance. The sustained release tablets were

prepared by Direct Compression and formulated using different drug: polymer ratios,

formulations such as FI to FI 5. Hydrophilic polymers like Hydroxy Propyl MefhyJ

Cellulose (HPMC), Carboxymethyl Cellulose (CMC) and Starch 1500 were used.

Kuniar2 et a i, (2010) worked on sustained release dosage fonns which are designed to

release a drug at a predetermined rate by maintaining a constant drug level for a specific

period of time with minimum side effects.

Saiikar, et a!., (2010) studied the effect o f Hydrophilic and Hydrophobic polymers on

Losartan Potassium matrix tablet and investigated the possibility o f sustaining the

Losartan Potassium release from matrix tablet, prepared by Hydrophilic and Hydrophobic

polymer. The preformulation studies were carried out the interaction between the drug


D E P A R T M EN T OF PHARMACEUTICS JAMIA HAMDARD

and polymers. The granules were punched into tablet, which was evaluated for physical

parameters.

IKiiniar3 et a l, (2010) 'formulated and Evaluated Didanosine enteric coated sustained

release tablet. Enteric coaled tablets o f Didanosine were developed to get resistance Irom

gastric juice when it presents in stoiiiach, because Didanosine is incompatible with

gastric juice. The tablets are prepared by using Wet Granulation Technique using

polymer Ethyl Cellulose STD 100 FP, Ethyl Cellulose Med 70 P, Ethyl Cellulose M ED

50 P and other excipients are Povidone Micro Crystalline Cellulose in different ratios.

Pa! et aL, (2010) formulated a sustained release matrix tablet containing micronized

carvediloi phosphate. Phosphate salt o f carvediloI possesses better aqueous solubility

than it’s free base. Hydroxy propyl substituted p cyclodextrin and poly ethylene oxide are

used as release modifying polymer to develop the matrix tablet. The comparative in vitro

evaluation between the developed micronized sustained release and noii-micronized

sustained release matrix tablet o f carvediloi are done. A significant increase in in vitro

drug release rate is observed in case o f the micronized product over the non micronized

one. The sustained release matrix tablet o f micronized carvediloi may be used as a once

daily formulation after relevant pharmacokinetic studies.

Ankit et al., (2010) introduced a validated method for the determination o f valsartan and

hydrochlorothiazide in tablets. Calibration curves for valsartan and hydrochlorothiazide

over concentration range o f 2 - 2 0 pg/ml were plotted and molar absorptivity for both the

drugs were calculated at both the wavelengths o f 270.5 nm (1-max o f

hydrochlorothiazide) and 231.5 nm (iso- absorptive point). The results of analysis have

been validated statistically followed by recovery studies. The value o f recovery studies

were ranging from 99.05-102.23% tor valsartan and 97.42-100.22% for

hydrochlorothiazide and were indicative for accuracy and precision o f the proposed

method. The results o f the assay are in good agreement with the labeled amount.



Niksim ei: al., (2 0 1 0 ) developed a simple first order derivative spectrophotoraetiic

method for simultaneous estimation of valsartan, amlodipinc besylcite and

hydrochlorothiazide in combined dosage form. The method employed was multi

wavelength method for analysis using metlianol; water (70:30) as a soJvent. The three

wavelengths 245, 265 and 279 nm were selected for estimation o f valsartan, amlodipine

besylate and hydrochlorothiazide respectively. Linearity was observed in the

concentration range o f 8-80 ),ig/ml 1 - 1 0 f.ig/ml and 2 - 2 0 j,ig/ml for valsartan, amlodipine

besylate and hydrochlorothiazide respectively. The recovery studies ascertained the

accuracy o f the proposed method and the results were validated as per ICH guidelines.

Prabakaran et aL, (2010) tbrmulated a sustained release matrix dosage form o f

Nifedipine, by using different polymers to achieve better bioavaiiability and also to

reduce dosing frequency and side-effects employing response surface methodology by

incorporating a 3-factor, 3-level Box-Behaken statistical design. Dependent variables are

the release retardant polymers such as HPMC K15M), HPMC EiO CR Prem., and

Sodium Alginate and Independent variables are the percentage drug release at 1 h,

percentage drug release at 8 h and hardness were studied. Box-Behnken response surface

plots were drawn, statistical validity o f the second order and quadratic models were

established and the optimized formulations was chosen based on feasibility and grid

search. The physical evaluation and in-vitro release studies were performed on all the

formulations and the data were fitted to different release kinetic equations such as zero

order, first order, Higuchi, Flixson Crowell and Korsemayer-peppas in terms o f V2 and n-

value. Validation of the optimization study with 13 confu'matory runs indicated high

degree of prophetic ability o f response surface methodology. From the confirmatory runs,

the optimized formulation showed gradual sustained release (best fit model—peppas,

n=0,44) by Fickian diffusion process. Their design facilitated the optimization o f

Nifedipine sustained release matrix dosage form to achieve better bioavaiiability.

Shantveer et al., (2010) described sustained release matrix tablets o f anti-hypertensive

drug propranolol hydrochloride. Hydroxy propyl methyl cellulose was used as a rate

retarding polymer where as lactose and dibasic calcium phosphates are used as diluent.

CHAPTER 2 LiTERATURE REVIEW 42


The results of study show that the rate o f propranolol hydrochloride release irom HPMC

matiiccs is mainly controlled by the drug - HPMC ratio. When the influence o f

excipients on the release o f drug was examined, the excipients lactose enhanced the

release rate o f propranolol hydrochloride, however the dibasic calcium phosphate (DCF)

demonstrated slower release rate. The prepared sustained release matrix tablets were

evaluated for various parameters like hardness, friability, uniformity o f weight,

uniformity o f drug content, i/i vitro drug release and short term stability studies. The

dissolution t5o% and t9o% values for tlie co-excipients were in the order o f lactosodibasie

calcium phosphate.

Pal et al., (2009) established a correlation between in vitro dissolution and in vivo

absorption data o f prepared sustained release Lellunomide microcapsules and compare

with conventional tablets o f Leflunomide( EravalOmg ).they took New-Zealand white

rabbit species for performing this study. The correlation ship was established according

to Drewe and Guitard basing on (degree A). Comparison o f cumulative in vitro

dissolution profile, in vitro dissolution constant ( K ) Vs AUC, Mean dissolution time Vs

mean residence time. The plasma dmg concentration vs/as measured with standard curve

equation and compared with the standard tablet data vi/hich showed all the formulations

have!hr to 4 hr extended T-max value confirming their sustained action. A ll formulated

micro spheres show identical pharmacological effect in comparison to standard

Leflunomide tablet. The parameters like dissolved fraction absorbed, MDT Vs MRT

andT85% revealed a significant in vitro in vivo correlation which substantiate the success

of correlation study.

Uddiii et aL, (2009) designed oral sustained release matrix tablets o f Ranolazine using

hydroxypropyl methylcelliilose (HPMC) as the retardant polymer and to study the effect

of formulation factors such as polymer proportion and polymer viscosity on the release o f

drug. In vitro release studies were performed in O.IN HCl for 12 hours. The release

kinetics was analyzed using the zero-order, first order, Higuchi and Korsmeyer-Peppas

equations to explore and explain the mechanism of drug release from the matrix tablets.

In vitro release studies revealed that the release rate decreased with increase in polymer



proportion and viscosity grade. The release kinetics indicated that the nature o f diug

release from the matrix tablets was dependent on drug diffosion and polymer relaxation

and therefore foilowed noii-Fickian or anomalous release.

Deslinmkii et aL, (2009) develojied Formulation and Evaluation o f sustained release

Metoprolol Succinate tablet using Hydrophilic gums as release modifiers. The objective

of this study was to design and evaluate ora! sustained drug delivery system for

Metoprolol Succinate using Natural hydrophilic gums such as Karaya giim and Xanthan

gum as a release modifier. Matrix tablets were prepared by wet grajiulation method and

were evaluated physical & chemical parameters, and Stereo Photography.

Smith et a!., (2009) developed sustained release matrix tablets o f Ondansetron

hydrochloride [5mg] formulated employing Hydroxy Propyl Methyl Cellulose polymer

and the sustained release behavior o f the tablets was investigated. Tablets were prepared

by wet granulation methods. The granules were evaluated for angle o f repose, biiilc

density and drug content. The tablets were subjected to thickness, diameter, weight

variation test, hardness, friability, drug content and in vitro release studies. Formulation

was optimized on the basis o f acceptable tablet properties and in vitro drug release.

Agnivcsii et ai., (2009) has designed, optimized, prepared and evaluated the dispersion

granules o f valsartan and formulation into tablets and the present work undertaken was

to enliance the solubility and dissolution rate tif valsartan an poorly water soluble

antihypertensive, by preparation o f solid dispersion granules which would additionally

allow easy compression into tablets.

Sayed et al., (2009) have incorporated IVl etc clop rami de hydrochloride (MCP) in

sustained release fonnulations by using different polymer ratios. These polymers were

hydroxypropy 1 methyl cellulose (HPMC), carboxymethylcellulose (CMC) and ethyl

cellulose (EC). Sodium starch glycolate (SSG) was added to some fbrmuiae in different

amounts in order to soften and/or disintegrate the tablets. Both direct compression and

granulation techniques were used to prepare the tablets. The dissolution profiles of the


D E P A R T M E N T OF PH ARM ACEUTICS JAMIA HAMDARD

tablets were constructed using the change-over method. The drug release involved a

combination o f both difflision and poiymer-chain relaxation mechanisms. The time

required to release 50% of MCP ranged fi-om 1 .2 to more tluin 8 hours. Direct

compression and dry granulation techniques produced sufficient sustaining o f the drug

release. However, the pellets made by wet granulation released MC!P in about 2 hrs, i.e.,

Pelletization spheronization technique was not effective in sustaining the drug,

Roni et siL, (2009) discussed about their in vitro evaluation o f their controlled release

dosage fonii containing alfijzosin hydrochloride. Binary mixer o f one hydrophilic

polymer (hydroxypropyl methylcellulose) and one hydrophobic polymer (ethyl cellulose)

was used in tablets prepared by direct compression, 32 factorial designs were chosen and

the amount of two polymers was taken as independent variables. The percent drug

released at 1,6, 12, and 20 h were selected as response. The main effect and interaction

terms were quantitatively evaluated using mathematical model. Dissolution data were

fitted to zero order, first order, and Higuchi’s release kinetics to evaluate kinetic data.

According to Korsrneyer's equation drug release followed both diffusion and erosion

mechanism in all cases.

Rs'iliinan et aL, (2009) initiated in the formulation of Metoclopramide hydrochloride

(MCP) in sustained release formulations. Metoclopramide hydrochloride (MCP) was

incorporated in 12 formulae containing different polymers and/or different polymer

ratios. These polymers were hydroxypropylmethyl ceiluiose (HPMC),

carboxymethylcellulose (CMC) and ethyl cellulose (EC). Sodium starch glycolate (SSG)

was added to some formulae in different amounts in order to soften and/oi- disintegrate

the tablets. Both direct compression and granulation techniques were used to prepare the

tablets. The physical properties were found to be satisfactory for all the formulae. The

dissolution profiles o f the tablets were constructed using the change-over method. The

drug release involved a combination o f both difflision and polymer-chain relaxation

mechanisms. The time required to release 50% of MCP ranged ficom 1.2 to more than 8

hours. Direct compression and dry granulation techniques produced sufficient sustaining

CHAPTER 2 LITERATimE REVIEW 4 5


of the drug release. However, the pellets made by wet granulation released MCP in about

2 hrs, i.e., Pelietization spheronization technique was not effective in sustaining the drug.

Basak et ai., (2008) benefited o f a sustained release dosage form, compared to a

conventional dosage ibrni, is the uniform drug plasma concentration and therefore

uriifbrm therapeutic effect. Over the past two decades, sustained release dosage tbirns

have made significant progress in terms o f clinical efficacy and patient compliance.

Matrix devices, due lo their chemical inertness, drug embedding ability and drug release

character, have gained steady popularity for sustaining the release o f a drug.

Preetfia et aL, (2008) described the effect o f mode o f incorporation o f superdisintegrants

like croscarmellose sodium, sodium starch glyeolate and crospovidone (polyplasdone XL

and XL-10) on dissolution of three mode! drugs with varying aqueous solubility, like

carbamazepine (poorly soluble), acetaminophen (sparingly soluble) and cetrizine HCl

(soluble) fi'om their respective tablet formulations prepared by wet granulation. The

disintegraiits were incoqjorated extragranularly or intragranularly or distributed equally

between the two phases. The dissolution test demonstrated that Crospovidone in general

was effective in improving the in vitro drugs release used in the study and generally

extragranular mode o f addition seemed to be the best mode o f incoi-poration, irrespective

of the solubility o f the main tablet component.

Jabereiiiaini, et aL, (2008) prepared and evaluated in-vitro o f sustained - release matrix

tablets o f Flutamide using synthetic and naturally occurring polymers. The sustained-

release matrix tablets of Flutamide were prepared by direct compression method using

different polymers. Cellulose ethers (HPMC and NaCMC), Natural gums (Guar and

Xanthan gums) and compressible Eudragits (RSPO and RLPO) and their combinations

were used in different ratios to examine their influence on tablet properties and drug

release profile.

Bhalekar et aL, (2008) studies the influence o f hydrophilic polymer (HPMC) and

hydrophobic polymer (Ethyl cellulose) on Nicorandil matrix sustained release tablet


D E P A R T M EN T OF PHA RM ACEUTICS jAM lA HAMDARD

which can release the dnig up to time o f 24 hrs in predetemiiiied rate. The formulation o f

Nicorandil matrix tablet was prepared by the polymer combination in order to get

required theoretical release profile. The influence o f hydrophilic and hydrophobic

polymer and granulation technique on Nicorandil was studied. The formulated tablet

were also characterized by physical and chemical parameters, The in-vitro release rate

profile should the higher concentration of F2 polymer in tablet, the combination of

hydrophilic and hydrophobic combination showed less result than use o f alone. The in-

vitro release data was well fit to Peppas tind Hixon crowd release kinetics.

kuniar ct aL, (2006) designed Eudragit-SIOO coated pellets for clironotherapeutic

delivery o f diltiazem hydrochloride by aqueous extmsion spheronization technique using

microcrystalline cellulose as a spheronizing aid and PVP K 30 as a binder. The friability

with glass spheres was below 1 .0 %, signifying the core pellets produced were sufficiently

hard. In vitro dissolution studies showed that the drug release fi'om the coated pellets

depended on the coat weights applied and pH o f the dissolution media. Since, diltiazem

hydrochloride is a drug, which exhibits a high solubility, it would be possible to minimize

drug release ftom the coated pellets below pH 7.0, and effectively release the drug at

colonic pH only with higher coat loads (15-20% weight gain).

Slioaib et al., (2006) developed a once-daily sustained release matrix tablet of ibuprofen

using hydroxypropyl rnethylcellulose (HPMC) as release controlling factor and to

evaluate drug release parameters as per various release kinetic models. In order to

achieve required sustained release profile tablets were dij'cctly compressed using Avicel

pH 10! and Magnesium stearate. The formulated tablets were also characterized by

physical and chemical parameters and results were found in acceptable limits. Different

dissolution models were applied to drug release data in order to evaluate release

mechanisms and kinetics. Criteria for selecting the most appropriate model were based on

linearity (coefficient of correlation). The dmg release data fit well to the Higuchi

expression. Drug release mechanism was found as a complex mixture o f diffusion,

swelling and erosion.



M ishra et a i , (2005) foiTniiJated and evaluated hydrophilic matrix tablets o f diltiazeni

hydrochloride to achieve a controlled and sustained drug release with reduced fi-equency

o f drug administration, reduced side effects and improved patient compliance. Matrix

tablets o f diltiazem hydrochloride were prepared using polymers like

hyroxypropylmethyl cellulose (HPMC K15, HPMC K4), sodium carboxymethyl

cellulose (SCMC) and Guar gum. All the batches were evaluated for thickness, weight

variation, hardness, drug content uniformity and in vitro drug release. The drug release

rates from matrix tablets were compared with marketed SR tbnnulations. Matrix erosion

and swelling studies were also carried out. The release kinetics and mechanism of drag

release by regression coefficient analysis and Peppas exponential release mode! equation

were also investigated. SCMC matrix tablets showed more hydration and erosion than

other matrix tablets. Tablets having HPMC K15 gave more sustained release than other

hydrophilic polymers studied and it was comparable with marketed SR tablets. Amount

of HPMC K15 and presence o f different diluents significantly affected the drug release.

They observed that all the fabricated tablets delivered the drug following Higiichi

diffusion mechanism.

Ojoe et aL, (2005) developed tablets containing theophylline (66.67%) based on a

Eudragit® RS 30D and NE 30D matrices containing 10% to 30% of either o f the polymer

were produced by compression method. The influence o f the different proportions o f

methacrylic esters, the use o f lactose and tribasic calcium phosphate as diluents and also

the effects o f the addition o f magnesium stearate as a lubricant on the theophyllixie

release, were studied. Physicochemical analyses and drug content was evaluated. In vitro

drug release studies were carried out in simulated gastric fluid without pepsin (pH 1 .2 )

and simulated intestinal fluid without pancreatin (pH7.5). A relatively prolonged release

of theophylline from the polymer matrices for a 7 hr release period was detected.

Magnesium stearate at 0.5% and Eudragit® NE 30D at 10% was considered a better

sustained release matrix compressed theophylline tablets comparing with Eudragit® RS

SOD in the same conditions (USP). Results from physicochemical analyses were in

accordance with specifications. Higuchi was the model that better fitted theophylline

kinetic, and diffusion controlled was involved.

CHAPTER 2 LITERATURE REVIEW | 4 8

DEPARTMENT OF PHARMACEUTICS fAMlA HAMDARD

Tabasideh et al., (2003) prepared matrix aspirin (acetylsalicylic acid) tablets with

ethylcellulose (EC), Eudragit R S I00 (RS), and Eiiclragit S I00 (S) were prepared by direct

compression. The release behaviors were then studied in two counterpart series o f tablets

with hardness difference o f three Kp units, and compared by non-linear regression

analysis. The release pattern for both the S-containing and RS-containing formulations

fitted best in Fliguchi model, and the proper equations were suggested. In the EC-

containing formulation, Higuehi and also zero-order models were probable models for the

release, and a combination equation for the release was suggested. In the Scontaining

formulation, the release profile was completely sensitive to the hardness change. In RS-

containing series, the slope of the release graph did not change due to the hardness

decrease, but the y-intercept or the lag time in release was decreased. In EC-containing

matrix tablets, both the slopes and the y-intercepts did not change by the decrease in

hardness, hi conclusion, EC with an amount as little as 10 percent in formulation could

make sustained-release aspirin tablets in which the release profile is not sensitive to

moderate changes in hardness.

Saravanan et aL, (2003) Developed hydroxypropyl methylcellulose (HPMC) based

cephalexin extended release tablet, which can release the drug for six hours in

predetermined rate. The influences o f HPMC, niicrocrystalline cellulose powder

(MCCP), granulation technique, wetting agent and tablet hardness on cephalexin release

from HPMC based extended release tablets were studied. The dissolution results showed

that a higher amount of HPMC in tablet composition resulted in reduced ding release.

Addition o f MCCP resulted in faster drug release. Tablets prepared by dry granulation

was released the drug slowly than the same prepared with a wet granulation technique.

Addition o f wetting agent in the tablets prepared with dry granulation technique showed

slower release. An increase in tablet hardness resulted in faster drug release.. The w vz7ro

release data was well fit in to Higuehi and Korsmeyer- Peppas model. The effect o f

storage on /« vi/ro release and physicochemical parameters o f successfiil batch was

studied and was found to be in acceptable limits.



Kubo et aL, (2003) developed an orai sustained delivery o f paracetamol from in situ

gelling gellaii and sodium alginate formuJations. The potential for the oral sustained

delivery o f paracetamol of two formulations with in situ gelling properties was evaluated.

In-vitro studies demonstrated diffusioii-cojitrolled release o f paracelamoi from the gels

ovei’ a peiiod o f six hrs. The bioavailability of paracetamol from the gels formed in situ in

the stomachs o f rabbits following ora! administration o f the liquid formulations was

similar to that o f a commercially available suspension containing an identical dose o f

paracetamo 1.

Mitchell et a!., (2003) developed a technique to enhance the dissolution rate o f poorly

soluble drugs with hydroxypropyl methylcellulose (BPMC) without the use o f solvent or

heat addition. Polymer and drug were blended, compressed into slugs on a tablet press or

into ribbons on a roller compactor, and then milled into a granular powder. Dissolution

testing of the milled powder was performed on 900 ml deionized water, 37 8 C. Drug

distribution vs. particle size was also studied. The compaction processes enhanced drug

dissolution relative to drug alone and also relative to corresponding loosely mixed

physical mixtures. The roller compaction and slugging methods produced comparable

dissolution enhancement. They claim that the compaction methods in their study may

provide a lower cost, quicker, readily scalable alternative tor formulating poorly water-

soluble drugs.

Silvina et a!., (2002) formulated and developed uncoated HPMC matrix tablets and

evaluated the relationship and influence o f different content levels o f microcrystalline

cellulose (MCC), starch, and lactose, in order to achieve a zero-order release o f

Diclofenac Sodium. In their study, HPMC matrix tablets o f Diclofenac Sodium using

microcrystalline cellulose (MCC), starch, and lactose were prepared by wet granulation

process. The dissolution profiles carried out in 900 mL 0.1 N HCl, and phosphate buffer.

They found no significant difference in diiig release between the hydrophilic matrices

when the HPMC concentration was modified in low percentage. Release kinetics o f

Diclofenac Sodium from these swollen matrices was principally regulated by starch (17

%) or lactose (17 %), even on the presence of MCC. Additionally, when starch (8.5 %)

CHAPTER 2 LlTEIMTLmE REVIEW 5 0

D E P A R T M EN T O F PHARM ACEUTICS |AMiA HAMDARD

and iactose (8.5 %) were mixed at lower concentration in a ratio i : i , MCC (5 % or 7, 5

%) appeared to control the drug release. The best-fit release kinetics was achieved with

the zero-order plot, followed by the Higuchi and first-order equations. Tire data obtained

proved that the ibrmuiations are useful for a sustained release o f Diclofenac, due to tlie

percentage released after 8 hours is nearly to 70 %. Compared to conventional tablets,

release of the model drug from these HPMC matrix tablets was prolonged; as a'result, an

oral release dosage form to avoid the gastrointestinal adverse effects was achieved.

Nataraj el al., (2001) targeted a simple precise accurate IJV Spectroscopic method as

theii' objective and validated for estimation o f valsartan in pure and pharmaceutical

dosage form. UV Spectroscopic method is based on measurement o f absorption of UV

light, the spectra of valsartan in methanol showed maximum wave length at 250nm and

calibration graphs were plotted over the concentrations ranging fi'om 2 - 2 0 (.ig/ml o f

valsartan with correlation coefficient 0.996 validation was perfomied as per ICH Q2 (R l)

guidelines for linearity, accuracy, precision and recovery. The limit o f detection (LOD)

and limit o f quantification (LOQ) were found to be 0.15 and 0.449 respectively by simple

UV Spectroscopy.

Tahara et a l, (1995) studied sustained release tablet matrices prepared using HPMC of

different viscosity and three different drugs of different solubility: methylparaben (MP),

propylparaben (PP) and U-78875. The tablets were prepared by granulating the active

compound with cornstarch and purified water, and blending the granulated material with

HPMC and lactose. The weight change o f the tablets during release was monitored.

Solubility results indicated that MF was soluble, PP was reasonably soluble and U-78875

was poorly soluble in the test medium. Increased with time indicating infiltration o f

medium into intersperse o f the tablet matrix. This was followed by swelling and erosion

of the matrix tablet. Surface erosion o f the tablet was also observed. The drug, release also

depended on the amount o f drug loaded and the solubility o f drug in the matrix,

Gudsoorkar et al., (1993) sustained release preparations provide an immediate dose

required for the normal therapeutic response, followed by the gradual release o f drug in


D E P A R T M EN T OF PHARM ACEUTICS JAMIA HAMDARD

amounts sufficient to maintain the therapeutic response for a specific (?xtended period o f

time. The major advantage o f this category is that, in addition to the convenience o f

reduced Irequency o f administration, it provides blood levels that are devoid of the peak-

and-valley effect which are characteristic o f the conventiona! ititermittent dosage

regimen.

Carmella et al., (19S4) studied the role o f disintegrants in the swelling process, which

was carried out by studying a number o f disintegrants available in the market. They used

various methods like X-ray analysis, microscopic observation, particle vohiirie increases

and hydration or salvations capacity. It was suggested that swelling could happen in ways

like capillary swelling and molecular swelling. So capillary and pore wet ability are

important in the development o f the swelling force. The whole process involved the steps

o f disintegration in the sequence o f water penetration, particle swelling of the

disintegrant, force development and bond disruption. Nevertheless, swelling is the

governing factor regarding the kinetics o f the whole process.

US Patent 0132839 and 0152620; compared and discussed that their pharmaceutical

composition of valsartan tablets dosage fomi is at 1 . 2 times more bioavailable than the

conventional valsartan capsule. The tablet fonnulation according to the invention

contains a disintegi’ant at concentration level o f 10-18 % based on total weight of the

composition. The higher amount of disintegrant ensures that the hydropliobic valsartan is

wetted well during the granulation stage. The tablet is readily dispersed as granules in the

dissolution medium resulting in a better dissolution and improved bioavailability over the

normal formulation. The invention does not, however, described methods to increase

solubility o f the valsartan itself in the gastric milieu; and therefore, the dissolution o f

valsartan in 0.IN HCl still remains low which results in low bioavailability (Ganter,

Sabina Maria 2002). .

2.3. Recent Developments in Na*io and Mkroeniulsion Drug Delives-}'

Kotta et a i , (2 0 1 2 ) gives a brief description about how oral nanoemulsions act as tool

for improvement of bioavailability of BCS class 2 and class 4 drugs. It also summarizes


D E P A R T M E N T OF PH A RM A CEU TICS JAMIA HAMDARD

the tlieoi7 behind the fonnation o f nanoglobules. This review clears the difference

between naiioernulsioii and lyotropic ‘microemulsion’ phase. It also covers the definition

o f nanoeniuision according to different authors. It gives a clear cut idea about all possible

methods for the preparation of nanoemulsion and the advantages and disadvantages o f

each method, It gives a brief description o f the stability problems o f nanoemulsion and its

prevention methods. This review also describes the most important and useful

characterization methods for nanoemulsion. It also presents a comprehensive update on

the patents and research works done in the arena of oral nanoemulsion.

Bali et al., (2011) developed an optimal and stable nanoemulsion of ezetimibe. The

release of drug from the nanoeniuision was highly significant as compared to the drug

suspension. The value o f total cholesterol in the group administered with the optimized

nanoemulsion formulation was highly significant with respect to the group administered

with the suspension o f the drug. The plasma concentration time profile of ezetimibe from

nanoemulsion represented greater im|?rovernent o f drug absorption than the marketed

formulation and simple drug suspension. The shelf life of the nanoemulsion was found to

be 5.94 years at room temperature. So the present study established nanoemulsion to be a

possible alternative for minimizing variation in bioavailability o f ezetimibe.

Shall et al., (2010) described that the nanoemulsion possesses various advantages such as

they do not show the problems o f inherent creaming, flocculation, coalescence and

sedimentation which are commonly associated with macroemuisions, NEs have a much

higher surface area than macroemuisions that make them an effective transport system.

Since NEs are formulated witli surfiictants, which are approved for human consumption,

they can be used orally. In the world o f nanomaterials, nanoemulsions hold great promise

since they can typically be formulated using considerably less surfactant than is required

for nanostructured lyotropic micro emulsion phases.

Mustafa et a i, (2009) investigated oil-in-water (o/w) nanoemulsion of atorvastatin for

enhancing its oral bioavailability. The area under the curve and maximum plasma

concentration o f atorvastatin nanoemulsion were found 9-fold and 5-fold higher,

CHAPTER 2 LfTERATlJRE REVIEW 53

DEPARTMENT OF PHARMACEUTICS ]AM1A HAMDARD

respectively when compared to simple atorvastatin suspension. The present study

illustrated the potential o f nanoemulsion dosage form in improving biopharmaceutic

performance of atorvastatin.

Tagne et a l , (2008) formulated a water-soluble narioernulsion o f the highly lipid-soluble

drug tamo,x.ifcn by microlluidization technique. The results suggested that nanoemulsions

o f tamoxifen, having mean particle sizes o f 47 nm, inhibited cell proliferation 20-fold

greater and increased cell apoptosis 4-fold greater in the HTB-20 breast cancer cell line.

Alves et a i , (2007) studied the in vitro skin penetration o f a drug model (iiimesulide)

from semisolid topical formulations containing nanospheres, naitocapsules or

nanoemulsion. They used nanoprecipitation, interfacial deposition and spontaneous

emulsification methods for preparation o f nanostmctured suspension. They incorporated

these nanocarrier systems in the hydrophilic gels and investigated in vitro skin

permeation through human skin using stripping technique and Franz-type diffusion cells.

They found that amount of nimesulide released into the stratum corneum (SC) from the

gel containing nanocapsuies (GNM~NC') and the gel containing nanospheres (GNM-NS)

was similar. On the other hand, for the gel containing nanoemulsion (GNM-NE), the

nimesulide was not quantified in SC, but it had directly permeated in the dermis.

Biriiss et al., (2007) investigated the permeation and the chemical stability o f 17-p-

estradiol, progesterone, cyproterone acetate and finasteride incorporated in an eucalyptus

oil containing microemulsion system. The formulations contained 1% (w/w) of the

steroid hormones. From these results a bicontinous structure was proposed for the

multicomponent system. However a cotrelation between the self diffusion of the

hormones in the vehicle and the transdermal flux was not indicated. By addition o f

certain polymers the skin permeation rates was improved with exception o f cyproterone

acetate.

Chan et aL, (2007) evaluated niicroemuslion-based phase transition systems for ocular

delivery o f pilocarpine hydrochloride. They used two non-ionic surfactants, sorbitan

mono laurate and polyoxyethylene sorbitan mono-oleate with ethyl oleate (oil

CHAPTER 2 LITERATUFÊ REVIEW 5 4

DEPARTMENT OF PHARMACEUTICS 1AMlA HAMDARD

component) and water. These systems underwent a phase change from ME to liquid

crystalline (LC) and to coarse emulsion (EM) with a change in viscosity depending on

water content. They found that phase transition micro emulsion is promising for ocu!ar

drug delivery as it pi'ovides the desired fluidity.

Ichikawa et a l, (2007) evaluated the effects of the formulation and particle composition

o f gadolinium (Gd) containing lipid nanoemulsion on the biodistribution o f Gd after its

intravenous (IV) injection in D(l)-179 melanoma-bearing hamsters for its application iii

cancer neutron-capture therapy. Biodistribution data revealed that Brij 700 and HCO-60

prolonged the retention of Gd in the blood and enhanced its accumulation in tumors,

Kliaiidavilli and Pancliagnula, (2007) investigated in vivo pharmacokinetic

performance of pachtaxe! (PCL) nanoeniulsion in order to acliieve penetration o f PCL

into deeper skin layers. Further, tiie same formulation was explored for peroral

bioavailability enhancement o f PCL. They concluded that developed nanoeniulsion

formulation was safe and eftective for both peroral and dermal delivery o f PCL.

Kuo et al., (2007) investigated whether a subcutaneous injection and/or transdermal

application of a nanoemulsion preparation of antioxidant synergy formulation (ASF)

would reduce tumor growth rate in a neuroblastoma xenograph mouse model. They found

that subcutaneous and/or transdermal application o f an ASF nanoemulsion preparation

was effective in reducing tumor growth rate in this neuroblastoma mouse model.

Reis et a l, (2007) prepared insulin-loaded alginate-dextran nanospheres by

nanoemulsion dispersion followed by triggered in situ gelation. Nanospheres were

characterized for mean size and distribution by laser diffraction_spectroscopy and for

shape by transmission electron microscopy. They found that alginate-dextran particles

suppressed insulin release in acidic media and promoted a sustained release at near

neutral conditions. Nanoencapsulated insulin was bio active as demonstrated by both in

vivo and in vitro bioassays.

Bouchemal et a l, (2006) investigated the role o f the polymeric membrane in the

protection o f the active dmg against damaging caused by external agents and to select the

monomer which helps in formulation of a stable formulation with the highest possible


D E P A R T M E N T OF PHARMACEUTICS JAMIA HAMDARD

payload o f the active drug. The colloidal suspensions of nanocapsules were obtained

using tlie combined interfacial polycondensatioii and spontaneous einulsification. They

concluded that the polyurethane based on HD offers good protection o f alpha-tocophero!

against damage caused by the temperature and IIV irradiation.

Clien el a l, (2006) constructed microemulsion-based hydrogel formulation for topical

delivery o f ibuprolen. Various microeraulsions were prejiared and evaluated for their skin

permeation through Ifanz diffusion cell. The results indicated that microemulsiori-based

hydrogel may be a promising vehicle for topical delivery o f ibuprofen.

Cruz et a!., (2006) established models to differentiate the kinetic release behavior o f

dnig models from nanocapsules, nanoeimilsion and nanospheres by physico-chemical

characterization and release experiments. Mathematical modeling o f the release profiles

was conducted, showing that the presence of the polymer increased the half-lives o f the

burst phases (5.9, 4.4 and 2.7 min) while the presence o f the oil increased the Imlf-lives o f

the sustained phases (288.8, 87.7 and 147.5 min) for nanocapsules, nanospheres and

nanoemulsion, respectively.

Freitas et al., (2006) developed a novel concept for the continuous, contact and

contamination-free treatment o f fluid mixtures with ultrasound. It was based on exciting a

steel jacket with an ultrasonic transducer, which transmitted the sound waves via

pressurised water to a glass tube installed inside the jacket. They concluded that this

novel technology offers a pharmaceutically interesting platform for nanodroplet and

nanoparticle production and is well suited for aseptic continuous processing,

Fu et al., (2006) enhanced the bioavailability and antimicrobial activity o f poorly water-

soluble glycerol . monolaurate (GML) by loading it in microemulsion system.

Microemulsions were prepared with GM L as oil, tweens as surfactant, and medium-and-

short chain alcohols at different ratio as cosurfactants. The effect o f the ratio o f surfactant

to cosurfactant on the stability of microemulsion was tested. The results showed that the

microemulsion was most stable when the ratio of surfactant to co surfactant was 3:2, the

suitable cosurfactant was pentanol to dodecane at 2:1. The area o f o/w microemulsion

region in pseudo-ternary phase diagram increased with increasing content o f potassium



sorbate. They concluded that GML loaded in microemulsion had much higher anti

microbial activity,

Garis et al., (2006) constructed U-type phase diagi'ams for cekcoxib ar;id fbrraulated

reverse microemulsions that were progressively and flilly dilutable with acfiieous phase.

Results indicated the enhanced solubilization of celecoxib in U-type nonionic

microemulsions.

Kogan and Garti, (2006) reviewed selected studies o f various microemulsions

containing certain drugs including retinoic acid, 5-fluorouracil, triptoiide, ascorbic acid,

diclofenac, lidocaine, and prilocaine hydrochloride in transdermal formulations. In

conclusion, they found microemulsions as an effective vehicle for the solubilization o f

certain drugs and as protecting medium for the entrapment o f drugs fiorn degradation,

hydrolysis, and oxidation. It also provide prolonged release o f the drug and prevented

irritation despite the toxicity o f the drug. Yet, in spite o f ali the advantages, the present

formulations lacked several key important characteristics such as cosmetic--permitted

surfactants, free dilution in water capabilities, stability in the digestive tract and sufficient

solubilization capacity.

Lv et al., (2006) investigated chloramphenicol microemulsion, composed o f Span 20,

Tween 20, isopropyl myristate (IPM) and water as potential drug delivery systems for eye

drops. Chbramphenicol in the common eye drops hydrolyzes easily. Here, the

chloramphenicol was trapped into the o/w microemulsions free o f alcohols. Its stability

w as investigated by the HPLC method in the accelerated experiments o f 3 months. They

revealed that the content o f the glycols in the microemulsion formulation was much

lower than that in the commercial eye drops at the end o f the accelerated experiments. It

implied that the stability of the chloramphenicol in the microemulsion formulations was

increased remarkably.

Pattani et aL, (2006) prepared and evaluated lipid nanoparticles and nanoemulsion o f

polymyxin B sulphate. They compared antimicrobial activity o f lipid nanoparicles and

nanoemulsion against a sensitive strain o f E. Coil. They concluded that the developed

lipid nanoparticles and nanoemulsion are promising delivery vectors for the antimicrobial

CHAPTER 2 LlTEflATURE REVIEV^ 57


drugs.

Poulseii et al., (2006) examined w/o microemiilsions t^^îcally used for preparation o f

sensors. The cores of the microerniilsion droplets were constituted by an aqueous

component consisting o f water, reagent monomer mixture, buffer salts, and the relevant

dyes and/or enzymes. The cores were encapsulated by a mixture o f the surfactants Brij30

and AOT and the resulting microemulsion droplets were suspended in a continuous

hexane phase. They tested and investigated how the monomers and the ratio between the

two surfactants affect the size o f the microemulsion droplets and the nnicroemulsion

domain. They found that the monomers in water had a profound effect on the

microemulsioii domain as well as on the size o f the microemulsion droplets.

Sintov and Boteer, (2006) evaluated the transdermal delivery potential o f diclofenac-

containing microemulsion system in vivo and in vitro. They found that the transdermal

administration o f the microemulsion to rats resulted in 8 -fokl higher drug plasma levels

than those obtained after application of Voltaren Emulgel. The transdermal fluxes o f

diclofenac were measured in vitro using skin excised from different animal species. In

three rodent species, penetration fluxes of 53.35±8.19 (furry mouse), 31.70±3.83 (hairless

mouse), 31.66±4.45 (rat), and 22.89±6.23 pg/cni^/h (hairless guinea pig) were obtained

following the application o f the inicroemulsion. These fluxes w'ere significantly higher

than those obtained by application of the drug in aqueous solution.

Spernatli et al., (2006) demonstrated the feasibility o f constructing phase diagrams with

a large isotropic regions capable o f being fully diluted with water. The microemulsions

were stabilized with mixtures composed o f phosphatidylcholine (PC) and nonionic

surfactant (polyoxyethylene-40 hydrogenated castor oil, HEC040) and short-chain

organic acid as cosurfactant/cosolvent. The presence o f a bJend o f PC and HEC040

seemed to have a synergistic effects, forming an isotropic region comprising 72% of the

area o f the phase diagram, in comparison to 20 and 50% in systems stabilized by PC and

HEC040, alone, respectively. The role of the PC molecules in the foixnation o f those

microemulsions was demonstrated by comparing three soy lecithins. Lecithin with a high

PC content formed larger isotropic regions with more “'free dilution” lines. Several

nonionic surfactants were investigated, yet only HEC040 seemed to have a packing

CHAPTER 2 LITEFlATUrÊ REVIEW 5 8

DEPARTMENT OF PHARMACEUTICS JAM (A HAMDARD

parameter suitable for the formation o f large isotropic Li-type systems.

Tom sic et aL, (2006) used srnall-angle X-ray scattering tecliiiique to study the structural

properties o f the quaternary microemiilsion. They prepared inicroemuision for ketoprofen

using Tween 40/Imwitor 308/isopropyl rnyristate/water. The present results indicated that

in the samples with the moderate to high concentration of water, the addition of smaller

amounts o f the ketoprofen did not change theii' inner structure significantly. They found

that all these changes in the inner stnjctnre o f the studied systems did not affect the trend

o f the drug release rates in this regime of water concentrations.

Yilm az and B orch art, (2006) evaluated the effect of positively charged oil/water

iianoeniulsions (FN) containing cerarnide 3B and naturally found SC lipids (PNSC) such

as ceramide 3, cholesterol, and palmitic acid on skin hydration, elasticity, and erythema.

Creams of PNSC were compared to PN creams. The formulations (PN, PNSC, and

NNSC) were prepared by high-pressure homogenization. After adding Carbopol 940 as

thickener, particle size and stability o f the creams were not significantly changed as

compared to the nanoemulsions. The studies were carried out on thi'ee groups, each with

14 healthy female test subjects between 25 and 50 years of age, using Corneometer 825,

Cutometer SEM 575 and Mexameter 18 for measurements o f skin hydration, elasticity,

and erythema of the skin, respectively. All fonnulations increased skin hydration and

elasticity. There was no significant difference between PNSC and Physiogel. However,

PNSC was significantly more effective in increasing skin hydration and elasticity than

PN and NNSC indicating that phyt.osphingosine induced positive charge. It was also

concluded that SC lipids and ceramide 3B are crucial for the enhanced effect on skin

hydration and viscoelasticity.

Ztiao et aL, (2006 a) prepared and characterized gelatin-containing microemulsion-based

organogels (MBGs) composed o f isopropyl myristate (IPM), AOT, Tween 85 and H2O,

loaded with and without a model drug (butenafine hydrochloride) by rheological

measurements and environmental scanning electron microscope (ESEM). Transparent

and homogeneous MBGs were formed when the concentration o f gelatin in the selected

w/o microemulsion was in the range o f 7.0-12.0 % v/v. The rheo logical properties such

as the yield stress, storage and loss moduli o f the MBGs samples increased and the

CH/\PTER2 LITERATURE REVIEW 5 9

DEPARTMENT OF PHARMACEUTICS jAMIA HAMDARD

network stiuctures o f the MBGs became more compact with increasing concentration o f

gelatin in the formulations. Furthermore, the addition of butenafine iiydrochioride to the

MBGs weakened the intercomiected network structures o f the MBGs systems. These

results showed that MBGs could be used as potential transdennal drug delivery vehicles.

Zliao et al., (2006 b) studied a microeinulsion vehicle as a possible matrix for

transdernial delivery o f theophylline. The existence of microemulsion regions were

investigated in pseudo-ternary phase diagi'ams, and various microemulsion formulations

were prepared using oleic acid, Cremophor RH 40/LabrasoI (1:2) and water. The results

showed that microemulsion system o f theophylline might be a promising vehicles for the

transdermal delivery o f theophylline.

Bidyut and Rajib, (2005) studied solubilization of water in mixed reverse micellar

systems with anionic surfactant (AOT) and nonionic surfactants (Brijs, Spans, Tweens,

IgepaJ CO 520), cationic surfactant (DDAB)-nonionic surfectants (Brijs, Spans, Igepal

CO 520), and nonionic (Igepal CO 520)~nonionics (Brijs, Spans) in oils o f diflerent

chemical structures and physical properties (isopropyl myristate, isobutyl benzene,

cyclohexane) at 303 K. The maximum water solubilization capacity in mixed reverse

micellar systems occurred at a certain mole fraction o f a nonionic surfactant.

Carli et al., (2005) applied nanoemulsified composite (NECTM) delivery system on a

very water insoluble iibideearenone drug. The resulting composite powder showed good

teclmological properties such as flowability; also good stability was observed. The sizes

o f the nanodroplets released from the systems were maintained same as the starting size

and also after a long storage. Furthennore very good biopharmaceutical properties were

originated, with water solubility concentrations up to 50-fold higher than pure

ubidecarenone and oral absorption in rats up to three-fold greater than standard

commercial products in terms of plasma levels and AUC.

Djordjevic et al., (2005) studied the influence of both formulation parameters and

vehicle structure on in vitro release rate o f amphiphilic drug diclofenac diethylamine

(DDEA) from microemulsion vehicles containing PEG-8 caprylic/eapric glycerides

(surfactant), polyglyceryl-6 dioleate (cosurfactant), isopropyl myristate and water. Low



water/isopropyl myristate apparent partition coefficient for DDEA as well as elevated

electrical conductivity and apparent viscosity values for the investigated microenuilsiori

formulations containing 1.16% (w/w) of DDEA, suggested that the drug molecules

predominantly partitioned in the water phase and most likely seif aggregated and

interacted with interfacial film. Release o f DDEA from the selected water-continuous

(W/0), oil-continuous (0/W) and balanced microernulsion.s was investigated using

rotating paddle dissolution apparatus modified by addition o f enhancer cell. A linear

diffusion o f DDEA through regenerated cellulose membrane was observed for the W/O

and 0/W formulations with the low content of dispersed phase. Non-linearity o f the drug

release profile in the case o f bicontinuous formulations was related to the more complex

distribution o f DDEA including interactions between the drug and vehicle. Moreover, the

obtained flux values for balanced microemulsions suggested that bicontinuous

microstructure hampered the release o f the arnphiphilic drug.

Gupta et a l, (2005) studied transdermal permeation o f 5 iluorouracil (5FU), a

hydrophilic drug encapsulated in AOT/water/lPM w/o microemulsions using a modified

keshary chein diffusion cell. Results revealed that the microemulsion interacted with a

component of the stratum corneum and perturbed its architectural structure. Preiiminary

toxicity studies indicated that the AOT/water/lPM w/o microemulsion were safe for the

transdermal permeation of 5-FU.

Lee et a!., (2005) developed an o/w microemulsion system to enliance the skin

permeability o f aceclofenac. Pseudo ternary phase diagrams were constructed to obtain

the concentration range o f oil (Labrafil), surfactant (Cremophor-ELP) and cosurfactant

(ethanol) for microemulsion formation. Terpenes were added to the microemulsion at a

level o f 5% and their effects on skin pemieation o f aceclofenac were investigated.

Limonene showed the best permeability enhancing capacity amongst all the terpenes

tested. ,

Shiokava et al., (2005) reported a novel microemulsions fomnulation for tumor-targeted

drug carrier o f lipophilic antitumor antibiotics, aclacinomycin A (ACM). Their findings

suggested that a folate-linked microemulsion was feasible for tumor-targeted ACM

CH A PTER 2 L IT E R A T U R E R E V I E W 6 1

D E P A R T M EN T OF PHARM ACEUTICS }AM1A HAMDARD

delivery. This study showed that foiate modifkation with a sufficiently long PEG chain

on emulsions was an effective way o f targeting emulsion to tumor cells.

Solans et aL, (2005) reviewed and summarized the formation, properties and apj)lications

of nanoemulsions (also referred to as minieniulsions, ultrafiiie emulsions, submicron

emulsions). Although most of the publications on either 0/W or W/O nanoemulsions

reported their formation by dispersion or liigh-energy emiilsification methods, an

increased interest was observed in tlie study o f nanoemulsion formation by condensation

or low-energy emulsification methods (based on the phase transitions that lake place

during the emulsification process). Phase behaviour studies showed that the size of the

droplets was governed by the surfactant phase structure (bicontinuous microemulsion or

lamellar) at the inversion poiiit induced by cither temperature or composition. Studies on

nanoemulsion formation by the phase inversion temperature (PIT) method showed a

relation between minimum droplet size and complete solubilization o f the oil in a

microemulsion bicontinuous phase independent o f the initial phase equilibria which was

either single or multiphase. The interesting application 'which v/as derived was an active

development in the use of nanoemulsions as formulations, lor controlled drug delivery

and targeting.

Siibraiiiaiiian et aL, (2005) developed and investigated microemulsion system

(isopropyl myristate/medium chain glyceride/polysorbate <SO/water) tor topical deHvery

o f celecoxib. The in vilro permeation rate ofcelecoxib through rat skin was determined

for microemulsions, microemulsion gel and cream by using the modified Frariz difflision

cell. Microemulsions enhanced the permeation rate ofcelecoxib up to 5 and 11 times as

compared to microemulsion gel and cream respectively.

Yifiiiaz and Borcfiart, (2005) focused on ffie preparation and characterisation o f

phytosphingosine (PS) containing PN (PPN) which served as colloidal carriers for the

dermal application o f ceramide IIIB (ClIIB) and the stratum conieum (SC) lipids

(PPNSC) such as ceramide III (CIO), cholesterol, and palmitic acid. The investigations

were conducted using appropriate emulsification and homogenisation processing

conditions to optimise PPNSC with regard to droplet size, physical stability, and

solubility o f PS, C lll and CIIIB. A decrease in droplet size was observed thi'ough eight



homogenisation cycles at a pressure o f 500 bars and a temperature o f 50 °C. Above tiiese

optimal values, an increase in droplet size was observed. When Li[3oid E-80 (LIE80) was

added to the oil phase, the solubility o f PS and ceramides increased, indicating some

interactions shown by DSC measurements. It was shown that PS was responsible for the

positive charge and thus supported the high physical stability o f PPNSC.

Aivarez-RomaHa et ai., (2004) evaluated how confocal laser scanning microscopy may

contribute to the determination o f the inechaoisms o f diverse skin penetration

enhancement strategies.

Aninon et al., (20§4) studied new microemulsion vehicle for lidocaine which was

composed of glyceryl oletite and polyoxyl 40 fatty acid derivatives

{surfactants)/tetraglycol (co-surfaetant)/isopropyl palmitate/water by constructing

pseudo-ternary phase diagrams at fixed eo-surfactant/surfactants (CoS/S) ratios.

Percutaneous penetration studies using rat skin showed that the transdermal flux o f

lidocaine was significantly improved by microerniilsion composed o f the glyceryl oleate-

PEG-40 stearate combination rather than glyceryl oleate-PEG~40 hydroxylated castor o il

By analyzing skin layers (epidermis and dermis) for lidocaine content, significant higher

concentrations were found after rats were treated in vivo with liquid microemulsions

(CoS/S = 1.8, 30 wt.% water) or patches compared to those measured after application o f

EMLA cream.

Aubruii et aL, (2004) prepared nano emulsions with a high shear device, which was less

constraining than spontaneous eniulsification procedures. They found that nanoemulsions

were easily acceptable in skin care due to their good sensorial properties (rapid

penetration and merging textures) and their biophysical properties (especially their

hydrating power).

Boinpally et a l, (2004) attempted to deliver cyelosporine A (CsA) across human cadaver

epidermis in vitro using colloidal systems like microemulsion, lecithin vesicles and

iontophoresis. Although, passive diffusion did not result in permeation o f quantifiable

amounts o f CsA, a nodal iontophoresis o f the negatively charged colloidal systems

facilitated the permeation. Lecithin vesicles were better than microemulsion for the



iontophoretic delivery o f CsA and appeared to have potential in site-specific

immimosuppression.

Brinie el aL, (2004) studied deoxycholate-AmB (D-AniB) in an immunocompetent and

neutropenic murine model of systemic candidiasis throagh microemulsions. D-AmB was

administered at the maximum tolerated dose o f I nig/kg whereas M-AmB was given at

the doses o f 1, 2 and 3 mg/kg. Doses were well tolerated due to their reduced toxicity.

Kaplan-Meier survival curves showed that the M~AniB treated group had a better

survival time than infected mice without treatment used as a control group. The Maiin-

Whitney W statistical test indicated that it reduced the percentage o f mortality and fongal

load in the most representative organs.

B iiiiia jd ad and Eastoe, (2004) studied the electrical conductivity o f D 2 0 -in-tt-heptane

microemulsions stabilized by cationic/nonionic surfactant mixtures as a fijnction o f D 2O

content, surfactant concentration and surfactant mixture composition. Qualitative

structural information was drawn fi-om a comparison between the measured conductivity

and that predicted by the charge fluctuation model lor spherical droplets. The

conductivity versus water content curves were found to be typical for water-in-oil

systems composed o f spherical droplets. From the effect o f blending nonionic surfactant

with DDAB on the measured conductivities, it was concluded that microemulsion

conductivity was independent of the concentration of cationic surfactant (DDAB).

Been et aL, (2004) synthesized a piperazine-based cationic surfactant, N, N dimethyl-N-

acryloyloxyundecyl piperazinium bromide (DAOUPB) by a two-step procedure. The

monomer was polymerised in two new microemulsion systems: (i) DAOUPB / water /

methyl Methacrylate (MMA):hydroxyethylmethaerylate (HEM A) and (ii) DAOUPB

/water / acrylonitrile with ethyleneglycol dimethacrylate (EGDM A) as the crossJinking

agent. Transparent solid polymeric materials were obtained by photo-initiated

polymerisation o f some o f these microemulsion compositions. Most o f the bicontinuous

microemulsions investigated gelled within 10 minutes resulting in transparent solid

polymers. The swelling o f the gels was highly sensitive to pH.


DEPARTMENT O F PHARMACEUTICS jAM IA HAMDARD

IDesai, (2004) studied microemulsion gels (MEGs) containing rofecoxib and rofecoxib

solid dispersion with PEG-4000 for rapid percutaneous absorption. Topical MEGs were

prepared by using neat rofecoxib as well as its solid dispersion to compare the efficacy o f

individual MEG with conventional gel (CG). MEGs containing rofecoxib-PEG 4000

solid dispersion exhibited higher drug penneation when compared to M EG containing

neat rofecoxib. MEGs containing rofecoxib-PEG 4000 solid dispersion exhibited faster

anti-inflammatory activity than CG.

Podlogar et siL, (20®4) prepared and examined pharmaceutically usable microemulsion

systems from water and isopropyl myristate with a constant amount of Tween 40 and

Imwitor 308 at a mass ratio of 1:1. Results o f conductivity, viscosity, density and

surface tension measurements confirmed the prediction o f a percolation transition to a

bicontiniious structure. DSC detected the degree o f water interaction with surfactants thus

identifying the type of microemulsion.

Porrasa et a i, (2004) studied the formation o f w/o nanoemulsions in water/mixed

nonionic surfactant/oil system by a condensation method. The appropriate ratio between

two surfactants was studied. The existence o f microemulsion, nanoemulsion and

emulsion regions was investigated by studying samples stability using backscattering

with time multiple light scattering technique. These studies allowed detenniiiation o f

zones where nanoemulsions were formed. For low water concentration, nanoemulsions

breakdown was attributed to ostwald ripening and for high water concentration,

nanoemulsions breakdown was attributed to coalescence.

Richter and Keipert, (2004) investigated the in vitro permeability o f androstenedione as

a highly lipophilic drug in excised bovine nasal mucosa, porcine cornea and the artificial

cellulose membrane Neplvophan. Results showed that structure and character o f different

membranes were considered to be mainly responsible for the different permeation

behaviour.

Sari et al.j (2004) found that the solubilities o f the levamisole HCl and abamectin were

higher in the isotropic MCMDG/sesame oil/water formulations than in equivalent

MCMDG/water formulations. In some formulations, the solubility o f levamisole HCl was



higher in the absence o f abarnectin than in combination with abarnectin. Isotropic

MCMDG/oil/water systems were obtained without the use o f co-suifactaiits. hicreasing

water content in the system did not proportionally increase the solubih'ty o f hydrophilic

drug. Solubilization of hydrophilic drug was affected by lipophilic drug in the presence or

absence o f SO and lipophilic drug solubility was affected by hydrophilic drug in tfie

absence o f SO. These systems were foiind to be suitable vehicles to deliver both

hydrophilic and lipophilic drugs and could be o f interest for pharmaceutical formulations.

Yuksel, (2004) investigated the influence o f chain length of the alkanes and alcohols on

water solubilization behavior o f microemulsions. Microemulsions were produced by

mixing different combinations o f the non-ionic surfactants Triton X-100 and Triton X-

405, «-alkanes (€ 5, C7, Cs and Cio) and benzene as oils, o-alcohols (C5 and C^} as

cosurfactants with water. The solubilization o f water in a particular microemulsion was

govtirned by the partitioning o f alcohols among oil, water and interfacial phases,

depending on the chain length and nature o f oil and alcohol, and their interaction with the

surfactant.

Sinks et aL, (2003) investigated the phase behaviour o f microernulsions stabilized by

mixtures containing a strongly amphiphilic double chain cationic surfactant with a

weakly amphiphilic short chain alcohol and found that microemulsions stabilized by

mixtures o f hydrogenated tallow di-methyl ammonium bromide (2HT) and weak propan-

2-ol (IPA) amphiphile, showed monolayer curvature and the extent o f microstructure

could be tuned.

Bisceglia and Acosta, (2003) measured layer bending rigidities for an AOT- water- iso -

octane micro emu Is ion by electric deformation and temperature dependent fluctuation

mode analysis. The values o f rigidity obtained by electric deformation method were

lower when computed with the fluctuation mode analysis. The dependence o f the rigidity

values on the methods o f calculation suggested that the mathematical approach based on

static method was more reliable than the dynamical one.

Escribaiio et aL, (2003) studied transdermal pemieation of four liquid formulations o f

1% (w/w) sodium diclofenac: three ternary solvent systems (M4, M5, M6) and one



rnicroemuLsion (M3) through human skin. A 1% (w/w) solution o f sodium diclofenac and

a conimercially available semisoiid preparation were tested as reference formulations.

The highest values o f permeability parameters were obtained with tbrrnula M4, which

contained transcutol 59.2%, oleic acid 14.9% and d-!imonene 5% (w/w) as permeation

enhancers. ,

He et aL, (2003) prepared paclitaxcl microemulsioiis with small particle size and

evaluated its hypersensitivity reaction. They found that paclitaxe! niicroeinulsions caused

less toxicity and had a longer circulation time in rats as compared to Taxol.

Junipiisg et at, (2fl03) evahiated injectable microemulsions o f vincristine (M-VCR) for

its pharmacokinetics, acute toxicity and antitumor effects and found that M-VCR was a

useful tumor targeting microemulsion drug delivery system.

Jiirkovic ct al., (2003) investigated the effectiveness of amphiphilic antioxidant ascorbyl

palrnitate against fi'ee radical formation in porcine skin, hi this study, three different

radicals were identified in UV irradiated porcine ear skin: two originated from sulphur

centred radicals, while the third was the carbon-centred acyl radical. Ascorbyl palrnitate

, applied on the skin decreased the level o f formation o f free radicals. 0 /W

microemulsions delivered ascorbyl palrnitate to the skin significantly better than W/O

microemulsions.

Mei et aL, (2003) developed controlled release delivery systems such as solid lipid

nanoparticle (SLN) and rnicroemulsion for triptohde and evaluated their transdermal

delivery capacity and anti-inflammatory activity. The results indicated that these SLN

dispersions and microemulsions could seiwe as efficient promoters for the triptolide

penetrating into skin. The anti-inflammatory activity o f SLN dispersion was stronger than

that o f rnicroemulsion in carrageenan induced rat paw edema.

Nandi et a l , (2003) reported the effect o f alkanols and cyclodextrins on the phase

behavior o f an isopropyl myristate rnicroemulsion system and studied the solubility o f

model dnigs, progesterone and indomethacin. A coixelation between the carbon numbers

o f the alkanol and water assimilation capacity in the microemulsions studied was

observed. Lsobutanol and isopentanol produced the best results. The addition o f


DEPARTMENT OF PHARMACEUTICS JAMJA HAMDARD

cyclodextrins showed no effect or had a negative effect on the microemulsion formation

based on the type o f cyciodextriii used. Isopropyl myristate-based inicroemulsion

systems alone could increase the solubility values of progesterone and indomethacin up

to 3300-foid and 500~fold, respectively, compared to that in W'ater. Flovi/evcr, the addition

o f cyclodcxtrins to the rnicroemulsion systems did not show a synergistic effect in

increasing the solubility values o f the model drugs,

Peltola et al., (2003) investigated microemulsions as delivery systems for estradiol.

Transdermai flux o f estradiol was detennined using Franz-type difftisioii cells and the

samples were analyzed by HPLC. The pemieation data showed that microemulsion

formulations increased estradiol flux 200—700 fold over the control, but permeability

coefficients were decreased by 5-18 times. The superior transdermai flux o f estradiol was

due to 1500-fold improvement in solubilization o f estradiol by microemulsions. The

results suggested the use o f microemulsions as potential vehicles for improved topical

delivery o f estradiol.

Rodriguez et at., (2003) investigated the phase behavior and structure o f sucrose

ester/water/oil systems in the presence o f long-chain cosurfactant (monolaurin) and small

amounts o f ionic surfactants by phase study and small angle X-ray scattering. In a water /

sucrose ester / monolaurin / decane system at 27”C, instead o f a three-phase

rnicroemulsion, lamellar liquid crystals were formed in the dilute region. The addition o f

small amounts of ionic surfactant increased the solubilization o f water in w/o

microemulsions. The solubilization o f oil in o/w microemulsions was not much affected,

but structuring was induced and a viscous isotropic phase was foiTned.

Spicliii et aL, (2003) selected o/w and w/o microemulsions as carrier systems for topical

delivery o f sodium ascorbyl phosphate, fhey showed that sodium ascorbyl phosphate

was stable in both types o f rnicroemulsion with no significant influence o f its location in

the carrier system. They obtained liquid microemulsions for topical application by adding

thickening agents. They found that presence o f thickening agent and the location o f

sodium ascorbyl phosphate in the rnicroemulsion influenced the in vitro drug release

profiles. When incoiporated in the internal aqueous phase, sustained release profiles were



observed. This study coirfirm ed m icroem ulsions as su itab le ca rrier sy stem s for top ical

application o f sodium ascorbyl |3hosphate.

Trotta et al., {2003 a) determined the significance o f ion pairing on the topical

permeation o f retinoic acid (R.A) using microeinulsions as delivery vehicles. Results o f

diftlision studies through polydimethylsiloxane membrane (PDMS) indicated that retinoic

acid permeation from ethanol-pH 6.4 buffer mixture significantly increased in the

presence o f counter ions. In order to develop alternative formulations for topical

administration o f R.A, microemulsions were evaluated as delivei'y vehicles. Experiments

w'Jth PDMS membranes showed decreasing permeabilities o f R.A fi'om microemulsions

in the presence of counter ions. This was related to the increased lipophilicity and

different vehicle membrane atrinity o f the ion pairs. The results suggested that 0 /W

microemulsions containing a counter ion can be used to optimise drug targeting without a

concomitant increase in systemic absorption.

Trotta et aL, (2003 b) prepared and evaluated nanoparticles o f gresiofulvin fi'om

dilutable microemulsions fay the solvent diffusion teciinique. Solvent-in-water

microemulsions were investigated by construction o f pseudoternary phase diagrams. The

displacement o f butyl lactate with an excess o f water fi'om the internal phase o f

microemulsions containing drug into the external phase, lead to successfiil fiibrication o f

drug nanosuspensions. They found increased dissolution rate o f gresiofulvin from

nanosuspensions.

El-iaithy and El-Sfiaboury, (2002) evaluated the influence o f vehicle on the release and

permeation o f fluconazole from cutina lipogels and gel microemulsion. They found better

antifungal activity with gel microemulsion as compared to cutina lipogels and concluded

that gel microemulsion were an excellent vehicle for fluconazole topical drug delivery.

Krtilgaard, (2002) reviewed that microemulsion vehicles have been frequently

employed over recent years to increase cutaneous drug delivery. He also reviewed that

microemulsion formulations have been shown to be superior for both transdermal and

dermal delivery o f particularly lipophilic compounds, but also hydrophilic compounds

CHAPTER 2 ■ LITERATURE REVIEW 6 9

DEPARTMENT OF PHARMACEUTICS jAMlA HAMDARD

appear to benefit from application in inicroeimilsioiis compared to conventional vehicles,

like hydrogels, emulsions and liposomes.

Paoliiio €t ill, (2002) investigated the potential application o f highly biocompatible o/w

rnicroenuilsions as topical drug carrier systems for the percutaneous delivery o f

ketoprofen. The topical carrier potentialities of lecithin-based o/w microemulsions were

compared with respect to conventional formulations, i.e. a w/o emulsion, a o/w emulsion

and a gel. The percutaneous adsorption o f the various topical formulations was evaluated

through healthy adult human skin. Ketoprofen-loaded microemulsions showed an

enhanced permeation througli human skin with respect to conventional formulations. The

human skin tolerability o f various microemulsion formulations was evaluated on human

volunteers. Microemulsions showed a good human skin tolerability.

Pitaksutcepong, (2002) studied the effect o f drag properties and method of loading

(sorption and encapsulation) on entrapment within poly(alkyl cyanoacrylate)

nanocapsules prepared by interfacial polymerisation o f biocompatible water-in-oiJ

microemulsions. Entrapment efficiency within the negatively charged nanocapsules (zeta

potential approximately 230 mV) was in tlie decreasing order o f cationic compound,

neutral compound and anionic compound. Only mijiimal differences for entrapment

efficiency were noted between sorption (addition o f the compound 4 h after initiation o f

the polymerisation) and encapsulation (addition o f the compound to rnicroemulsion prior

to polymerisation).

Taha et aL, (2002) utilized data mining, computer-aided molecular modeling, descriptor

calculation and multiple linear regression techniques to produce statistically significant

and predictive models for o/w and w/o microemulsions. The generated models were

statistically cross-validated and were found to be o f significant predictive power.

Furthermore, the resulting models allowed better understanding o f the process o f

microemulsion formation.

Yang et aL, (2002) developed a novel transdermal formulation, microemulsion for

aceclofenac to increase its skin permeability. Microemulsion was prepared by



sjjoiitaneous emulsificatioii method. Skin permeation o f microemulsion from

microemulsion formulation was higher than that o f cream.

Actiar}'a ct a l, (2001) investigated microemulsification of eiicalyptol / polyoxyethylene

(4) iauryl ether (Brij-30) /ethanol / water. The phase behaviours o f the mixed system in

pseudotemary and tetrahedral representations were examined to understand the

topological nature of the multicoinponent mixtures. Phase volumes of the heterogeiieous

combinations were estimated to understand the mixing efficacy of die coixibinations.

Aivarez-Figiieroa ct a l, (2001) investigated the effectiveness of transdermal

administration of methotrexate (MTX) by iontophoretic delivery from two type o f

hydrogel and passive delivery from two types of microeinulsions. The results showed that

both hydrogels and microemulsions may be of value for the topical administration o f

MTX in the treatment o f psoriasis.

Hamoudal et al., (2 0 0 1 ) tested a novel non-ionic surfactant nanoemulsion designated

8 N 8 for its biocidal activity. One percent 8 N8 produced effective bactericidal activity,

virucidal activity and ilingistatic activity against all tested strains o f bacteria, virus and

fungi respectively in 15 minutes. The rapid and non-specific inactivation o f vegetative

bacteria and enveloped viruses, made 8 N 8 a potential candidate for use as a topical

biocidal agent.

Wu et a!., (2001 a) prepared a variety o f w/o nanoemulsions using SpanSO, TweenSO,

olive oil and water. The nanoemulsions were tested for their ability to facilitate transport

o f a model hydrophilic solute, inulin, across hairless and hairy mouse skin and hairy rat

skin following topical in vitro application. The rate and extent o f inulin transport across

hairy mouse skin was found to be highly dependent on HLB of the surfactant mixture in

the nanoemulsion, Nanoemuslions prepared using mixtures with lower HLB exhibited

significantly higher rate and extent o f transport. More importantly, transport o f inulin

from nanoemulsions was independent o f animal skin characteristics such as stratum

corneum thickness and follicle-type.

W u et al., (2001 b) formulated expression plasmids encoding chloramphenicol ,

acetyltransferase (CAT) or human interferon-a2 cDNA in w/o nanoemulsions and

CHAPTER 2 LITERATURE RRVIEW | 71

DEPA R T M EN T OF PHARMACEUTICS JAMIA HAMDARD

applied to murine skin. The results suggested that w/o nanoeimilsions can be used to

facilitate transfection o f follicular karatinocytes in vivo.

Baroli et a i , (2 (MI0 ) evaluated microemulsions as delivery veliicles for the topiccil

administration o f 8 -MOP. The ability o f the systems to deliver 8 -MOP into and through

the skin was evaluated in vitro using newborn pig-skin. The in vitro permeation data

showed that the nove! microemulsions increased the 8 -MOP total penetration through the

skin by order o f 1.9-4.5, as compared with 1PM. These results suggested that the studied

microemulsion systems may be appropriate vehicles for the topical delivery o f S-MOP.

CesclieJ et a i, (200©) investigated the diffusion and permeation o f Salbia desoleana

Atzei & Picci (S. desoleana) essential oil through porcine buccal mucosa. Topical

formulations (microemulsions, hydrogels and microemulsion hydrogels) were prepared

for application to the buccal mucosa. The diffusion o f the oil through the membrane was

detemiined by evaluating the amount o f essential oil components present in the receiving

solution, the flux and the permeation coefficient (at the steady state) in the different

formulations at set intervals. Qualitative and quantitative detemiinations were done by

gas chromatographic analysis. All the formulations allowed a high pemieability

coefficient in comparison with the pure essential oil. In particular, the components with a

terpenic structure (b-pinene, cineole, a-tetpineol and linalool) had the highest capacity to

pass through the porcine buccal mucosa when compared to the other components (linalyl

acetate and a-teipinil acetate).

Kreilgaard et al., (2000) investigated the influence o f structure and composition o f

microemulsions (Labrasol/Pluroi Isostearique/isostearylic isostearate/water) on their

transdermal delivery potential o f a lipophilic drug (lidocaine) and a hydrophilic model

drug (prilocaine ' hydrochloride), and compared the drug delivery potential o f

microemulsions to conventional vehicles. Self-diffusion coefficients determined by

pulsed-gradient spin-echo NMR spectroscopy and T1 relaxation times were used to

characterise the microemulsions. Transdermal flux o f lidocaine and prilocaine

hydrochloride through rat skin was determined in vitro using Franz-type diffusion cells.

Microemulsions increased transdermal flux of lidocaine up to 4 times compared to a

conventional oil-in-water emulsion, and that o f prilocaine hydrochloride almost 10 times

CHAPTER 2 LITERATUFÊ REVIEW 1 72


compared to a hydrogel. The increased transdermal drug deiivei'y from microemulsion

forniulaiioris was found to be mainly due to the increased solubility o f drugs and

appeared to be dependent on the drug mobility in the individual vehicle.

Sclieriiind et aL, (20(10) investigated environmentally responsive dmg delivery systems

as interesting development. Example of such development involved the use o f

thermosetting microemulsions as delivery systems tor periodontal anesthe.sia. In this case,

a block copolymer liquid microemulsion containing lidocaine and prilocaine u'as

designed to form a gel after in vivo administration to the periodontal pocket.

Chung et a i, (1999) produced thermoresponsive polymeric block copolymer micelles

based on poly (N isopropylacrylamide) and poly (butylmethacrylate) containing

adriamycin.

Park et a!., (1999) investigated the possibility for parenteral delivery o f flurbiprofen

without chemical modification using a phospholipid-based microernulsion system. They

concluded that the microemulsion system might be applicable to formulate the parenteral

dosage form o f poorly water-soluble flurbipro fen without chemical modification.

Sodermsin sand Nyde, (1999) investigated microemulsions prepared by mixing the

double chained surfactant didodecyldimethylammonium sulfate (DDAS), water,

dodecane and hexadecane using NM R self-diffusion approach. At low surfactant-to-oil

ratios the aggregates were discrete and spherical in shape. As the surfactant-to-oil ratio

was increased, the surfactant aggregates changed shape and the structure evolved into a

bicontinuous microemulsion. In extracting this information from the experimentally

detennined self-diffusion coefficients, authors made use o f reduced diffusion

coefficients, which were obtained by dividing the observed diffusion coefficients with the

values pertaining to diffusion in a system. The observation that the reduced diffusion

coefficients for the surfactant and oil were equal at high surfactant-to-oil ratios indicated

that the structure was truly bicontinuous over distances on the order o f mm.

Trotta, (1999) reported the release rates o f indomethacin Irom microemulsions

containing water, isopropyl m>ristatc, lecithin, lysolecithin and alcohol. Depending on

the composition, the microemulsions transformed on contact with the release medium




into emulsions, liquid ctystals, or remained as microemulsions. The release rates were

found to be dependent on the size o f the disperse phase after dilution with the release

medium, and on the alcohol used in the fonnuiation. Microemulsions that remained

transparent after dilution produced rate constants lower than those that transformed into

emulsions. The rate constant for the microemulsion that transformed into liquid crystals

were not calculated because of the broad dispersion, but the percentage o f drug released

was much lower than those from the others systems.

Maicolnisoii et aL, (1998) reported that raicroemulsions prepared from ethyl esters and

triglyceride oils exhibited a significant increase in solubilization over the corresponding

micellar solution. Light scattering and phase inversion temperature studies suggested that

the structure o f the microernulsion was sensitive to the oil being used. The smaller

molecular volume oils generally permitted the interfaciai surfactant monolayer in much

the same way as a cosurfactant, causing an alteration, presumably a dilution, o f the

relatively concentrated polyoxyethylene region close to the hydrophobic core, thereby

destroying one o f the main loci o f drug solubilization and counteracting any advantages

encountered due to the high solubility of the drug in the bulk oil.

Cortesi et siL, (1997) reported that the microemulsion formulation for Camptothecin

(CPT) was optimal when Labrasol, Plurol isostearate and isostearyl isostearate was used

as surfactant, cosurfactant and oil components respectively. CPT solubility in

microemulsion was, in fact, at least five-fold higher with respect to that displayed by the

micellar solution of polysorbate and almost 23 fold higher than that in water.

2.4. Commercial preparations of psoralen;

Brand Name

Manademi tab

Manaderrn oint

Melanocyl tab

Chromalin tab

Composition

Psoralen 10 mg

Psoralen 10 mg/g

Psoralen 10 mg

Psoralen 10 mg

Coiiipaiiy

Wyeth

Wyeth

Franco India

Smith stanistreet

pharmaceuticals Ltd,

DEPARTMENT OF PHARMACEUTICS ]AMIA HAMDARD

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